In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein

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The causal reasoning is that Zika infection is linked to the development of microcephaly in newborns and Guillain-Barré syndrome in adults. With no clinically approved antiviral treatment for ZIKV, the need for the development of potential inhibitors against the virus is essential. In this study, we aimed to screen phytochemicals from papaya (Carica papaya L.) against NS5 protein domains of ZIKV. Methods Approximately 193 phytochemicals from an online database (IMPACT) were subjected to molecular docking using AutoDock Vina against the NS5-MTase protein domain (5WXB) and -RdRp domain (5U04). Results Our results showed that β-sitosterol, carpaine, violaxanthin, pseudocarpaine, Δ7-avenasterols, Rutin, and cis-β-carotene had the highest binding affinity to both protein domains, with β-sitosterol having the most favorable binding energy. Furthermore, ADMET analysis revealed that selected compounds had good pharmacokinetic properties and were nontoxic. Conclusions Our findings suggest that papaya-derived phytochemicals could be potential candidates for developing antiviral drugs against ZIKV. However, further experimental studies using cell lines and in vivo models are needed to validate their efficacy and safety. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/12-655", "name": "In silico screening for potential inhibitors from the phytocompounds..." } } ] } Home Browse In silico screening for potential inhibitors from the phytocompounds... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Kumaree KK, Anthikapalli NVA and Prasansuklab A. In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.12688/f1000research.134956.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] Kishore Krishna Kumaree https://orcid.org/0000-0002-0693-6366 1,2 , Naga Venkata Anusha Anthikapalli 3 , Anchalee Prasansuklab https://orcid.org/0000-0001-8884-3077 1,2 Kishore Krishna Kumaree https://orcid.org/0000-0002-0693-6366 1,2 , Naga Venkata Anusha Anthikapalli 3 , Anchalee Prasansuklab https://orcid.org/0000-0001-8884-3077 1,2 PUBLISHED 25 Jun 2024 Author details Author details 1 College of Public Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand 2 Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 3 Department of Chemistry, Akkineni Nageswara Rao College, Gudivada, Andhra Pradesh, 521301, India Kishore Krishna Kumaree Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Naga Venkata Anusha Anthikapalli Roles: Data Curation, Methodology, Project Administration, Resources, Software, Validation, Writing – Review & Editing Anchalee Prasansuklab Roles: Formal Analysis, Funding Acquisition, Resources, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Bioinformatics gateway. This article is included in the Emerging Diseases and Outbreaks gateway. This article is included in the Cheminformatics gateway. Abstract Background The Zika virus (ZIKV) infection has emerged as a global health threat. The causal reasoning is that Zika infection is linked to the development of microcephaly in newborns and Guillain-Barré syndrome in adults. With no clinically approved antiviral treatment for ZIKV, the need for the development of potential inhibitors against the virus is essential. In this study, we aimed to screen phytochemicals from papaya ( Carica papaya L. ) against NS5 protein domains of ZIKV. Methods Approximately 193 phytochemicals from an online database (IMPACT) were subjected to molecular docking using AutoDock Vina against the NS5-MTase protein domain (5WXB) and -RdRp domain (5U04). Results Our results showed that β-sitosterol, carpaine, violaxanthin, pseudocarpaine, Δ7-avenasterols, Rutin, and cis-β-carotene had the highest binding affinity to both protein domains, with β-sitosterol having the most favorable binding energy. Furthermore, ADMET analysis revealed that selected compounds had good pharmacokinetic properties and were nontoxic. Conclusions Our findings suggest that papaya-derived phytochemicals could be potential candidates for developing antiviral drugs against ZIKV. However, further experimental studies using cell lines and in vivo models are needed to validate their efficacy and safety. READ ALL READ LESS Keywords Molecular docking, Zika virus, Papaya, AutoDoc Vina Corresponding Author(s) Anchalee Prasansuklab ( [email protected] ) Close Corresponding author: Anchalee Prasansuklab Competing interests: No competing interests were disclosed. Grant information: C2F (Secondary Century Fund) Postdoctoral Fellowship, Chulalongkorn University, Bangkok 10330 The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Kumaree KK et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Kumaree KK, Anthikapalli NVA and Prasansuklab A. In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.12688/f1000research.134956.2 ) First published: 13 Jun 2023, 12 :655 ( https://doi.org/10.12688/f1000research.134956.1 ) Latest published: 25 Jun 2024, 12 :655 ( https://doi.org/10.12688/f1000research.134956.2 ) Revised Amendments from Version 1 We are grateful for the reviewers' comments that helped us improve the second version of the manuscript. The changes done to this version are mentioned below: We expanded the introduction to provide a comprehensive overview of Carica papaya . Recent prevalence and incidence data on Zika virus (ZIKV) infections from 2022 and 2023 were included, and references for control inhibitors were corrected and updated. The manuscript was thoroughly reviewed for grammatical and syntax errors, and abbreviations were consistently applied throughout. "Zika" was used uniformly throughout the manuscript for consistency. Higher-quality images replaced low-resolution ones, and figure captions were updated for better visualization. The conclusion highlights novel findings, impacts, and study limitations, such as the need for further experimental validation. Additionally, a typing error in the PDB structure for NS5-RdRp was corrected. The manuscript has been thoroughly checked, and the reviewer's comments have significantly improved it. We are grateful for the reviewers' comments that helped us improve the second version of the manuscript. The changes done to this version are mentioned below: We expanded the introduction to provide a comprehensive overview of Carica papaya . Recent prevalence and incidence data on Zika virus (ZIKV) infections from 2022 and 2023 were included, and references for control inhibitors were corrected and updated. The manuscript was thoroughly reviewed for grammatical and syntax errors, and abbreviations were consistently applied throughout. "Zika" was used uniformly throughout the manuscript for consistency. Higher-quality images replaced low-resolution ones, and figure captions were updated for better visualization. The conclusion highlights novel findings, impacts, and study limitations, such as the need for further experimental validation. Additionally, a typing error in the PDB structure for NS5-RdRp was corrected. The manuscript has been thoroughly checked, and the reviewer's comments have significantly improved it. See the authors' detailed response to the review by Arumugam Vijaya Anand See the authors' detailed response to the review by Luis Marquez-Dominguez READ REVIEWER RESPONSES Introduction Zika virus (ZIKV), belonging to the Flaviviridae family, is a mosquito-transmitted virus that infects humans by biting Aedes mosquitos ( Aedes aegypti ). 1 Though the ZIKV was first reported in 1947 in Uganda, the severity of this virus was globally noticed during its outbreak in the years 2015–2017 in Brazil, and later the infection spread to 46 other countries. 2 , 3 Furthermore, the recent outbreak was associated with severe neurological abnormalities such as microencephaly in foetuses, Guillain-Barré syndrome in adults and newborns due to infected mothers. 4 – 6 Even though the pandemic waves have subsided, sporadic detections of Zika infections continue to be reported in several parts of the world, with the virus becoming endemic to those regions. 7 , 8 Henceforth, continuous surveillance and research are essential to develop an effective treatment. ZIKV is an enveloped virus characterized by the presence of a single-stranded RNA genome. 5 , 9 The genome of ZIKV encodes a single polyprotein (~3400 amino acids), which is translated to three structural proteins (capsid-C, pre-membrane/membrane-prM, and envelope–E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) using host and viral proteases ( Figure 1 ). 10 Despite the significant efforts of the scientific community, there is currently no specific therapy available for treating ZIKV infection, making developing such antivirals a critical priority. 11 , 12 Antivirals that could target protein structures involved in genome replication, viral fusion, and RNA synthesis can be highly effective against the ZIKV. Among all the proteins expressed by ZIKV, the most significant and most conserved protein is the non-structural-5 or NS5, which is the polymerase enzyme; it consists of two major domains: RNA methyltransferase (MTase) at its N-terminus and RNA-dependent-RNA polymerase (RdRp) at its C-terminal. 13 RdRP is an essential protein domain for initial viral replication, whereas the MTase domain is responsible for RNA capping of the viral genome. The structure of NS5 is exclusive to ZIKV and has no similarity with the host system, which makes it a unique target for inhibitors against ZIKV. 14 Figure 1. The surface, structural, and non-structural proteins of the ZIKV are illustrated in the diagram, which highlights the virion components and the genomic RNA. The ZIKV polyprotein is composed of seven non-structural proteins (NS1, NS2A, NS2B, NS3 protease and helicase domains, NS4A, NS4B, NS5 methyltransferase, and RNA polymerase domains) and three structural proteins (C, M, and E). In addition, NS5 methyltransferase and RNA polymerase domains’ structures were retrieved from PDB (Protein Data Bank) databases. Continued clinical research is necessary to discover new antivirals. Considering the lower toxicity of plant-derived compounds, 15 , 16 they serve as promising leads for developing novel antiviral agents against various viruses, including Zika, through various mechanisms involving inhibition of viral replication, modulation of host immune response, and blocking viral entry into host cells. 17 – 21 Molecular modeling techniques are widely used to study the dynamics, energy, and interactions between biomolecules, including proteins. These techniques are used extensively to study protein-ligand interaction and to predict the drug’s binding mode within the protein’s binding site. Through in silico analysis, several studies have identified potential phytochemicals and their impact on human target proteins. 22 – 25 Henceforth, for this project, we have carried out in silico molecular docking analysis for potential anti-ZIKV compounds from Carica papaya ( commonly referred to as papaya), an edible tropical fruit well-known for its many medicinal properties. 26 C. papaya , belonging to the family Caricaceae, is a tropical fruit-bearing plant known for its rich content of vitamins, enzymes, and antioxidants. 27 Papaya contains bioactive substances, including alkaloids, flavonoids, and phenolic acids, which have been reported to exhibit various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, and antiviral activities. 27 , 28 C. papaya has demonstrated significant therapeutic potential and has been used in home remedies for centuries. 29 In several Asian countries, its seeds and peels are utilized to treat stomach ailments, bacterial infections, and inflammations. Moreover, a few studies have reported its antiviral attributes and immunomodulatory properties, but limited research has explored the specific constituents of C. papaya that exhibit antiviral effects. Previous in silico studies have documented the potential therapeutic effects of papaya in various human diseases, 30 – 32 including an earlier study on identifying inhibitory compounds (e.g., luteolin) that targeted the dengue virus’s NS2B/NS3 protease (DENV). 33 , 34 Given that ZIKV and DENV are members of the same family, we proposed to virtually investigate small molecules from papaya with possible targeting ZIKV NS5 protein domains, and to the best of our knowledge, no prior studies have investigated this possibility. The current study aims to conduct a virtual screening of bioactive molecules from papaya, followed by an ADMET (absorption, distribution, metabolism, elimination, and toxicity) assessment. Through molecular docking analysis using Autodoc Vina, we identified compounds that showed a promising binding affinity with the ZIKV’s NS5 protein domains (MTase and RdRp). Thus, they constitute potential drug targets, and our results may contribute toward developing effective treatments against this public health priority. Methods Preparation of molecule database and ligand preparation Phytocompounds of C. papaya were selected from the plant database IMPACT and previously published literature (see the Underlying data, Supplementary Table S1). 34 – 38 The ligands’ 3-dimensional (3-D) structures were retrieved from the PubChem database. The ligands underwent a series of adjustments, such as the addition of polar hydrogens, adding charges, and conducting energy minimization using PyRx Virtual Screening Tool software (v-0.8) (RRID:SCR_018548) with the default parameters. 39 Receptor selection and preparation The crystal structures of the ZIKV proteins were retrieved from the PDB (Protein Data Bank) database . These included the SAH-binding site of the NS5-MTase, and NS5 RNA-dependent RNA polymerase with their PDB entry 5WXB 40 and 5U04, 41 , 42 respectively. Sinefungin and Sofosbuvir were included as the reference inhibitors for the NS5-MTase and NS5 RdRp, respectively. 14 , 43 – 45 In accordance with standard protocol, the protein structures were treated as receptors. At the start of docking, the receptor protein was optimized by removing any unrelated substructure. Then, the side chains in the protein structure were corrected using default settings like adding hydrogens and removing water molecules. The Molprobity server evaluated selected proteins’ stereo-chemical properties and Ramachandran graph. 46 Chimera 1.16 (RRID SCR_004097) generated any residues missing in the selected target protein. After removing nonstandard heteroatoms, polar hydrogens and Gasteiger charge were added. Next, the structural aspects of all targets were enhanced using the steepest descent (100 steps) and conjugate gradient algorithms (0 steps) with an Amber force field (Amber Ff14SB). 46 The energy-minimized proteins were then converted into ‘pdbqt’ format using AutoDock Tools 1.5.7 (RRID SCR_012746) by AutoDock. Ligand and receptor molecular docking Docking was performed with Autodock Vina, 47 , 48 as described in a previous study. 49 Briefly, the grid box’s dimensions were fixed at XYZ = 30 Å × 30 Å × 30 Å XYZ = 30 Å × 30 Å × 30 Å which was found to be the best size for the default exhaustiveness (= 8), and the ligand binding site was positioned in the middle of the grid box. AutoDock Vina version 1.1.2 (RRID:SCR_011958) was used to calculate each ligand’s binding energy and pose against the selected protein receptors. Each ligand’s best interaction energy scores (kcal/mol) were ranked and plotted against the reference inhibitor. The results obtained are limited to nine binding modes. The log file included a list with increasing binding energies and binding modes. The binding modes were viewed using the BIOVIA Discovery Studio visualizer - v21.1.0.20298 (Dassault Systemes BIOVIA, Discovery Studio, 2021, SanDiego). 50 ADMET and drug-likeness evaluation The compounds’ molecular properties and drug-like characteristics were assessed using “Lipinski’s Rule of Five” as the basis of analysis. 51 First, 19 phytocompounds were analyzed regarding their physicochemical properties, drug-likeness, toxicity, and ADMET properties using ADMETlab 2.0 and SwissADME . In addition, the physicochemical features of compounds, including lipophilicity (log P), solubility (log S), and polar surface area and volume (PSA), were predicted. The mentioned parameters are necessary as they influence how a drug interacts with transport proteins and enzymes involved in drug clearance. Results molecular docking For the molecular docking analysis, around 193 compounds found in papaya were docked against the two domains of ZIKV protein NS5 MTase (5WXB) and RdRp (5U04). 35 As positive ligands, Sinefungin against the NS5-MTase and Sofosbuvir against the NS5-RdRp were docked. Sinefungin had a binding affinity of -8.1 kcal/mol, whereas the binding affinity for Sofosbuvir was -7.4 kcal/mol. Binding affinity is an essential preliminary parameter for assessing a potential candidate drug. Therefore, first of all, we assessed the binding affinity of the candidate drug and compared it with the positive controls (Sinefungin and Sofosbuvir against 5WXB and 5U04, respectively). The initial docking analysis helped narrow it down to 19 shortlisted compounds that showed higher affinity than their respective positive ligands, as shown in Figure 2 . Figure 3A shows the heat map of the binding affinity of the ligands, with the lowest energy/highest affinity corresponding to red color, whereas the blue color indicates the highest binding energy or/lowest affinity. Figure 2. Structural representation (2D) of the ligands shortlisted for having greater binding affinity to the receptor than the positive ligands used (Sofosbuvir and Sinefungin for 5U04 and 5WXB, respectively). Figure 3. Docking results of phytocompounds from C. papaya against target NS5 protein domains NS5-MTase (5WXB) and NS5-RdRp (5U04) of Zika virus (A) The Heatmap showing the binding affinities of best-docked compounds with target protein domains. Blue indicates low binding affinity and red indicates high binding affinity. (B) Venn diagram representing the commonly shared best-docked ligands (compared to respective positive control ligands) with the target protein domains. For the MTase domain (5WXB), rutin has the strongest binding affinity with a binding energy of -9.80 kcal/mol, followed by Δ7-avenasterol (-9.20 kcal/mol), β-sitosterol (-9.10 kcal/mol), cis-β-carotene (-8.90 kcal/mol) and pseudocarpaine (-8.90 kcal/mol). On the other hand, the weakest binding affinity is shown by γ-carotene, with a value of -7.00 kcal/mol. Whereas for the RdRp domain of NS5 (5U04), the ligand Δ7-avenasterol shows the highest binding affinity, followed by dehydrocarpaine-II and pseudocarpaine. Several ligands (rutin, carpaine, Δ7-avenasterol, β-sitosterol, pseudocarpaine, cis-β-carotene, violaxanthin) showed a better binding affinity with both the domains of NS5- protein ( Figure 3B ). Figure 4 shows the 3D and 2D structure of the common ligands, which showed higher docking ability towards both the domains of NS5 protein; however, the remaining ligand complexes are mentioned in the Underlying data, Figures S1 and S2. 35 Among these bispecific compounds, rutin showed the highest binding affinity for both protein domains, followed by carpaine. Figure 4. 2D and 3D interaction views of the best-docked phytocompounds from C. papaya , illustrating their binding modes with ZIKV NS5 protein domains. (A)-(G) display the complexes with MTase-5WXB, (H)-(N) present the complexes with RdRp-5U04, and (O)-(P) show the complexes with positive controls sinefungin and sofosbuvir. Hydrogen bonds and hydrophobic interactions play a critical role in molecular docking, and these interactions are key components in identifying potential drugs. As mentioned in Table 1 , rutin forms the highest number of hydrogen bonds involving 14 amino acid residues (ARG84, GLY86, LYS182, ARG213, CYS82, GLU218, GLU149, GLU149, GLY109, THR104, GLU111, HIS110, HIS110, LYS61) and the bonding distance ranging from 2.27 to 3.08 Å; however, rutin had no hydrophobic interaction with the MTase domain ( Figure 4 ). In hydrophobic interactions, Δ7-Avenasterol and cis-β-Carotene form the highest number (5) bonds with the MTase domain. Ligands interaction with the RdRp domain of NS5 ( Table 2 , Figure 4 ) shows that rutin has formed the highest number of hydrogen bonds (ARG794, ARG794, THR795, THR796, GLY793, SER798) and three hydrophobic interactions. α-Carotene forms the highest number of hydrophobic interactions with the RdRp domain and has no hydrogen bonding. Table 1. Docking results of identified potential phytochemical compounds from C. papaya against NS5- MTase domain (5WXB). Ligand name Hydrogen bond Hydrophobic bond Number Amino acids involved Distance (Å) Number Amino acid Type Sinefungin (Positive Ligand) 5 ARG84, GLY85, GLU111, THR104, VAL130 2.03, 2.43, 2.16, 2.12, 2.52 0 - - Rutin 14 ARG84, ARG213, GLY86, LYS182, CYS82, GLU218, GLU149, GLU149, GLY109, THR104, GLU111, HIS110, HIS110, LYS61 2.76, 2.55, 3.08, 2.27, 2.33, 2.34, 2.73, 2.62, 2.96, 2.64, 2.90, 2.57, 2.61, 2.81 0 - - Riboflavin 9 SER56, GLY86, TRP87, GLY81, GLU111, GLY58, CYS82, GLY86, ASP146 2.20, 2.56, 2.67, 2.55, 2.60, 2.34, 2.39, 2.26, 3.66 0 - - Carpaine 3 SER56, SER150, GLY58 1.98, 2.81, 2.90 0 - - Pseudocarpaine 3 HIS110, GLY81, GLY812 2.57, 2.54, 2.63 1 HIS110 Pi-Sigma Violaxanthin 2 TRP87, CYS82 2.47, 2.61 3 LEU16, PHE24, PHE24 Alkyl, Pi-Alkyl, Pi-Alkyl Dehydrocarpaine I 2 GLU149, SER150 4.86, 2.71 0 - - β-Sitosterol 1 SER56 2.81 4 HIS110, LYS105, ILE147, ILE147 Pi-Sigma, Alkyl, Alkyl, Alkyl Δ7-Avenasterol 1 ASP146 3.56 5 LYS105, VAL132, ILE147, ILE147, PHE133 Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl cis-β-Carotene 0 - - 5 LYS105, LYS105, ILE147, ILE147, HIS110 Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl Table 2. Docking results of identified potential phytochemical compounds from C. papaya against NS5-RdRp domain (5U04). Ligand name Hydrogen bond Hydrophobic bond Number Amino acids Distance (Å) Number Amino acids Type Sofosbuvir (Positive ligand) 2 TRP420, ALA408 3.05, 3.43 - - - Rutin 6 ARG794, ARG794, THR795, THR796, GLY793, SER798 2.24, 2.36, 3.05, 2.76, 2.06, 2.28 3 ARG794, MET806, ALA408 Pi-Alkyl, Pi-Alkyl, Pi-Alkyl Zeaxanthin 3 ASN612, ASP665, GLY664 2.12, 2.15, 2.55 3 VAL606, ILE799, MET806 Alkyl, Alkyl, Alkyl Violaxanthin 2 VAL339, VAL339 2.42, 2.99 6 ARG739, VAL742, PRO744, PRO744, ARG794, PRO744 Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Alkyl β-Sitosterol 1 LYS403 2.44 3 VAL404, ARG483, PHE400 Alkyl, Alkyl, Pi-Alkyl β-Carotene-5,6-epoxide 1 GLY738 3.04 7 ALA423, ARG739, VAL742, ARG794, ARG794, TRP797, TRP797 Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl, Pi-Alkyl Citroxanthin 1 GLY738 3.04 7 ALA423, ARG739, VAL742, ARG794, ARG794, TRP797, TRP797 Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl, Pi-Alkyl All-trans-Neoxanthin 1 ASN407 2.22 7 ARG739, VAL742, PRO744, RG794, ARG794, TRP797, TRP797 Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl, Pi-Alkyl Pseudocarpaine 1 TRP420 2.42 0 - - Dehydrocarpaine II 1 ALA408 2.37 0 Carpaine - - - - - - γ-Carotene 0 - - 13 TRP797, ALA423, LEU480, ARG739, AL742, VAL742, PRO744, ARG794, ARG794, VAL404, TRP479, TRP797, TRP797 Pi-Sigma, Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl, Pi-Alkyl, Pi-Alkyl cis-β-Carotene 0 - - 8 ALA423, LA482, ARG483, RG483, TYR453, TRP479, TRP479, TRP479 Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl, Pi-Alkyl, Pi-Alkyl, Pi-Alkyl β-Carotene 0 VAL606 5.12 5 VAL606, ILE799, ILE799, MET806, TYR609 Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl Antheraxanthin 0 ARG739 3.99 6 ARG739, VAL742, ARG794, ARG794, TRP797, TRP 797 Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl, Pi-Alkyl β-Cryptoxanthin 0 - - 5 ALA423, ARG739, VAL742, PRO744, TRP797 Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl α-Carotene 0 - - 11 TRP420, TRP420, LYS421, ARG739, VAL742, ARG794, ARG794, TRP420, TRP420, TRP420, RP797 Pi-Sigma, Pi-Sigma, Alkyl, Alkyl, Alkyl, Alkyl, Alkyl, Pi-Alkyl, Pi-Alkyl, Pi-Alkyl, Pi-Alkyl 7-Avenasterol 0 - - 3 VAL404, ALA423, TRP420 Alkyl, Alkyl, Pi-Alkyl Prediction of ADMET analysis ADMET and drug-likeness evaluation provide insight into the properties of drugs based on their chemical structure. The best-docked ligands ( Figure 2 ) were analyzed for their pharmacokinetic properties. The evaluation criteria were based on solubility, gastrointestinal absorption (GI), blood-brain barrier (BBB) permeability, and violation of Lipinski’s rules. (BBB - permeability = YES or > 0.1); (GI - absorption = high); (Carcinogenicity = 0 to 0.3); (PAINS alert = 0) and (Lipinski’s violation = 0). All the compounds mentioned in Figure 2 were screened through ADMET for their suitability as a drug. The screening through ADMETLab 2.0 revealed that several compounds were approved under Lipinski criteria. BBB values reflect the ability of the ligands to cross the brain barrier, with a higher score value indicating greater permeability. β-Sitosterol has the highest BBB penetration with a score of 0.84, suggesting effective crossing. Carpaine showed to have poor penetration with a BBB score of 0.01. BBB values ranged between 0.01 and 0.001, indicates poor barrier crossing. Riboflavin, rutin, and all-trans-neoxanthin displayed moderate BBB permeability values ranging from 0.111 to 0.444, while several had BBB penetrations below 0.1, suggesting the limited ability to cross the BBB (see the Underlying data, supplementary Table S2. 35 Table S2 ( Underlying data 35 also signifies the ligands’ permeability based on Caco-2 cell permeability values, which translates to intestinal epithelium permeability. For example, β-sitosterol had the highest Caco-2 cell permeability value at -4.756, signifying improved intestinal permeability. On the other hand, carpaine showed poor intestinal epithelium permeability of -4.985. Table S2 ( Underlying data 35 ) suggests ligands and their respective Lipinski’s rule of five compliance. Among these ligands, β-sitosterol, violaxanthin, riboflavin, all-trans-neoxanthin, dehydrocarpaine-I, dehydrocarpaine-II, and β-carotene are Lipinski’s-rule-of-five compliant and are considered to be drug-like compounds. Discussion Emerging viruses such as Dengue, Zika, Ebola, SARS-CoV2, and other infectious viruses demonstrate that the current antiviral therapeutic regimen is insufficient for these pathogens. 52 The coronavirus 2019 (COVID-19) pandemic further highlighted this inadequacy. Vaccine development is a time-consuming and lengthy process, which also faces the challenges of large-scale administration. Moreover, the faster-evolving attribute of RNA viruses also makes it challenging to develop a particular antiviral treatment, 53 one such RNA virus, Zika, remains a global concern. Zika-related disorders are mainly found in infants but can also affect adults. Zika-related disorders reported in adults were the cases of Guillain Barre’ Syndrome, 54 Myelitis, 55 Meningoencephalitis, 56 and Uveitis. 57 Currently, no approved drugs and no vaccines are available for treating ZIKV infection. Plant-derived natural compounds are promising alternatives for treating infections with minimal side effects. Medicinal plants are the richest source of new drugs, including antivirals targeting several human ailments. Previous clinical studies have demonstrated the successful inhibition of Dengue infection by papaya extract. 58 , 59 Phytochemical screening of papaya has been reported to constitute several compounds, which have potent therapeutic effects against several human diseases, such as inflammation, oxidative stress, antiviral and hypoglycemia. 60 , 61 Since Zika and Dengue belong to the same family of viruses, we hypothesized that papaya could also serve as the source for identifying potential inhibitors against ZIKV infection. In this context, in the present study, we have performed molecular docking to identify possible lead compounds from papaya against NS5 protein domains of the ZIKV. Initially, we screened 193 papaya-derived phytochemicals to know their molecular docking potential with the NS5 protein domains of the ZIKV. Our analysis revealed seven compounds (β-sitosterols, carpaine, violaxanthin, rutin, β-carotene, pseudocarpaine, and Δ7-avenasterol) that exhibited bispecific docking activity against both NS5 domains, with higher docking scores compared to their respective positive ligands (Sinefungin and Sofosbuvir against 5WXB and 5U04, respectively) ( Figure 3A ). The MTase activity of the ZIKV NS5 protein plays a crucial role in the replication and spread of the virus. 62 Hence, inhibiting this activity can be an effective strategy to prevent the virus from spreading. Previous studies explored small molecule inhibitors and RNA-based inhibitors against ZIKV infections. For instance, Sinefungin is a small molecule that has been shown to inhibit the MTase activity of several flaviviruses. 63 However, the study showed a low potency of Sinefungin on NS5 of ZIKV compared to other flaviviruses’ MTase domain; additionally, the toxicity associated with the particular drug had raised concern about its use. 64 Hydrogen bonding and hydrophobic interactions are crucial in facilitating significant ligand binding at the active site residues of the receptor in docked complexes. 65 In addition to hydrogen bonds and hydrophobic interactions, other non-covalent interactions such as alkyl-alkyl, pi-alkyl, and pi-pi interactions also play significant roles in ligand binding. Alkyl-alkyl interactions stabilize the complex via van der Waals forces, while pi-alkyl and pi-pi interactions enhance stability and binding affinity through aromatic ring stacking and hydrophobic effects. However, we primarily focused on hydrogen bonds and hydrophobic interactions due to their critical roles in ligand binding affinity and stability within the receptor's active site. 65 , 66 The bioactive compounds in this study were found to form hydrogen bonds and hydrophobic interactions with MTase. In the present study, flavonoid compounds, like rutin, showed the highest binding affinity to the NS5-MTase domain (5WXB), followed by riboflavin. Rutin formed a complex that entirely occupied the protein through 14 hydrogen bonding interactions with no hydrophobic interactions, and riboflavin interacted with the NS5-MTase through nine hydrogen bonds ( Table 1 , Figure 4 ). Moreover, the interacting residues were identified as essential residues of the substrate binding of the MTase. 67 The observed hydrogen bonding interactions between the selected compounds from papaya and MTase suggest that these compounds may effectively occupy the substrate binding site of MTase, making them promising lead compounds for drug development against ZIKV infection. Furthermore, the present study also indicates that phytocompounds from papaya showed several forms of strong and stable bonds like carbon-hydrogen, pi-alkyl, van der Waals, covalent, hydrophobic, and electrostatic bonds with the receptor ligands ( Tables 1 and 2 ). The ZIKV RdRp constitutes another important target for inhibiting Zika viral replication. 68 ZIKV RdRp consists of two binding sites, the first one being the active site (formed by Asp535, Trp797, and Ile799), while the other side is the allosteric or N pocket, which contains the priming loop that is essential for stabilizing the initiation complex and releasing new dsRNA. 69 In this study for docking to the RdRp domain (5U04), the result reveals that rutin, has the highest number of hydrogen bond interactions (with ARG794, ARG794, THR795, THR796, GLY793, SER798) and hydrophobic interactions (involving ARG794, MET806, ALA408 amino acids) compared to the positive ligand, Sofosbuvir ( Table 2 , Figure 4 ). Phytosterols are naturally occurring plant molecules with a structure similar to cholesterol, 70 and they have been demonstrated to possess the antiviral activity of several sterols against the spike protein of the COVID-19 virus and influenza-A virus. 63 , 71 Our study identified several phytosterols, including β-sitosterol and Δ7-avenasterol, demonstrating potent inhibitory affinity ( Figure 3A ). Earlier studies have also shown the potential health benefits, including antiviral effects of β-sitosterol, which has been shown to reduce the infectivity of the hepatitis-B virus and HIV, possibly by hindering the attachment of viruses to host cells. 72 Another study on HIV patients found that the combination of β-sitosterol and β-sitosterol glycoside helped maintain stable CD4 cell counts and significantly reduced plasma viral loads. 73 Alkaloids have also been shown to inhibit DNA and/or RNA synthesis in multiple viruses, including human coronavirus and herpes simplex virus. 74 – 76 Our docking studies identified alkaloids like carpaine and pseudocarpaine ( Figure 3A ) with higher binding affinity to both target protein domains compared to positive ligands. Besides, another alkaloid dehydrocarpaine-II had a good binding score (-8.8 kcal/mol) only towards the protein NS5- RdRp domain. Therefore, binding to the RdRp domain may help inhibit normal virus replication. Meanwhile, the carpaine-5U04 complex had no interaction with the protein through hydrogen or hydrophobic bonding. Apart from it, several carotenoids had also shown good binding affinity to both domains of NS-5. Especially, carotenoids such as α-carotene, β-carotene, citroxanthin, β-cryptoxanthin, γ-carotene, violaxantin, and zeaxanthin showed higher binding affinity to the NS5-RdRp than NS5-MTase. Carotenoids have a variety of applications, including anticancer, anti-inflammatory, and antioxidant properties, as well as anti-obesity. 77 – 79 Moreover, carotenoids also possess antiviral properties. 80 – 82 Also, recent studies have proven the antiviral properties of carotenoids against COVID-19. 83 Conducting in silico analyses on compounds to assess their absorption, distribution, metabolism, and excretion (ADME) properties is critical as part of drug development. 84 Failure to accurately simulate these attributes or assess any toxicities may cause inhibitors to fail the screening process and thus fall outside its criteria for approval. 85 BBB penetration is important when developing drugs to treat central nervous system (CNS) conditions. 86 Cytochrome P450 (CYP) isozymes metabolize drugs, fatty acids, steroids, bile acids, and carcinogens. 87 Approximately 75% of phase-1 drug metabolism processes involve CYP enzymes. 88 CYP inhibitor and substrate scores were calculated in this metabolism, and the result shows that the shortlisted compounds are non-substrates and non-inhibitors of CYP enzymes ( Underlying data , supplementary Table S2 35 ). Our ADMET analysis ( Underlying data , supplementary Table S2 35 ) demonstrated that 19 of the best-docked compounds ( Figure 2 ) had nontoxic properties. Lipinski’s rule of five was violated for ten compounds ( Underlying data , supplementary Table S2 35 ). However, the remaining compounds (carpaine, dehydrocarpaine I, dehydrocarpaine II, pseudocarpaine, Δ7-avenasterol, all-trans-neoxanthin, riboflavin, β-sitosterol, and violaxanthin) were found to be acceptable candidates based on Lipinski’s rule of five. Zika virus infection remains a public health concern due to the lack of specific antiviral therapies. Our study investigated the potential of C. papaya extracts as a source of ZIKV inhibitors. In silico molecular docking identified seven compounds with favorable binding energies to both the MTase and RdRp domains of the ZIKV NS5. These findings suggest their potential as the inhibitors of viral replication. However , in silico methods require in vitro and in vivo validation to confirm their efficacy against ZIKV infection. Furthermore, these compounds' bioavailability and toxicity profiles need to be assessed to ensure their safety and effectiveness as potential drug candidates. These results offer a promising approach for developing natural, safe, and effective antiviral drugs against ZIKV, potentially filling the current therapeutic gap and contributing to global health efforts against the virus. Data availability Source data Protein Data Bank: crystal structure of ZIKV MTase in complex with SAH. Accession number 5WXB; https://doi.org/10.2210/pdb5WXB/pdb . Protein Data Bank: Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase https://doi.org/10.2210/pdb5U04/pdb . Underlying data Zenodo: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein. https://doi.org/10.5281/zenodo.12057456 . 35 This project contains the following underlying data: • 3D structure-Papaya compounds-IMPACT.zip (3D structures of all the compounds downloaded from IMPACT database) • NS5- protein.zip (3D structures of both the protein domains of NS5 protein) • supplementary Figures.docx • Supplementary Table S1.xlsx (Molecular docking result of all the downloaded compounds) • supplementary Table S2.xlsx (ADMETlab 2.0 information of the shortlisted compounds) Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgements Kishore K. Kumaree extends thanks to the Secondary Century Fund (C2F) Postdoctoral Fellowship, Chulalongkorn University, Bangkok, Thailand, for supporting this research project. References 1. 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Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 13 Jun 2023 ADD YOUR COMMENT Comment Author details Author details 1 College of Public Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand 2 Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 3 Department of Chemistry, Akkineni Nageswara Rao College, Gudivada, Andhra Pradesh, 521301, India Kishore Krishna Kumaree Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Naga Venkata Anusha Anthikapalli Roles: Data Curation, Methodology, Project Administration, Resources, Software, Validation, Writing – Review & Editing Anchalee Prasansuklab Roles: Formal Analysis, Funding Acquisition, Resources, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information C2F (Secondary Century Fund) Postdoctoral Fellowship, Chulalongkorn University, Bangkok 10330 The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 25 Jun 2024, 12:655 https://doi.org/10.12688/f1000research.134956.2 version 1 Published: 13 Jun 2023, 12:655 https://doi.org/10.12688/f1000research.134956.1 Copyright © 2024 Kumaree KK et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Kumaree KK, Anthikapalli NVA and Prasansuklab A. In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.12688/f1000research.134956.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 25 Jun 2024 Revised Views 0 Cite How to cite this report: Marquez-Dominguez L. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.168075.r295619 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v2#referee-response-295619 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Aug 2024 Luis Marquez-Dominguez , Instituto Mexicano del Seguro Social, Puebla, Mexico Approved VIEWS 0 https://doi.org/10.5256/f1000research.168075.r295619 The authors have made several corrections. However, in this revision, I have some comments or doubts that could better enrich the authors' work. Methods : The plant database is IMPPAT: Indian Medicinal Plants, Phytochemistry And Therapeutics, not ... Continue reading READ ALL The authors have made several corrections. However, in this revision, I have some comments or doubts that could better enrich the authors' work. Methods : The plant database is IMPPAT: Indian Medicinal Plants, Phytochemistry And Therapeutics, not IMPACT. Molecular Docking Results : Second Paragraph : The text "Figure 3A shows the heat map of the binding affinity of the ligands, with the lowest energy/highest affinity corresponding to red color, whereas the blue color indicates the highest binding energy or/lowest affinity." should be changed to "Figure 3A shows the heat map of the binding affinity of the ligands. The red color represents the lowest energy/highest affinity, while the blue color indicates the highest energy/lowest affinity." Page 5, Last Paragraph : The statement "rutin forms the highest number of hydrogen bonds involving 14 amino acid residues" is incorrect. Rutin interacts with 12 residues but generates two hydrogen bonds with two residues, Glu149 and His110. It is suggested to correct this. If the author wants to emphasize that there are two hydrogen bonds, they could indicate this by writing "2-E149," where the number corresponds to the hydrogen bonds formed with the residue. It is also recommended to list the amino acids in ascending order and use the one-letter nomenclature for the amino acids. Figure 3 : Order the red molecules at the top and the blue molecules at the bottom. This will allow a quick evaluation of which molecules are potential inhibitors. In the column titles, put the name or function of the enzyme and leave the PDB ID in parentheses. Figure 4 : The control should be the first to appear, as it is the reference for comparison. Reduce the number of structures presented. Select only two for each protein and two that inhibit both. For example, for 5WXB: Rutin and delta 7 avenasterol; for 5U04: delta 7 avenasterol and dehydrocarpaine. The other couplings can be included in the supplementary material. If possible, all structures should present the same pose to facilitate comparison of inhibitors for the same enzyme. Table 1 : Modify the amino acid nomenclature to one letter. Be careful with the number of amino acids. For example, pseudocarpaine lists Gly812, but 5WXB has only 195 amino acids. Remove the column title "Hydrophobic bond" and replace it with "Non-covalent interactions." Table 2 : Similar suggestions to Table 1. Mention in the text that the crystallized protein 5U04, according to the PDB sequence, has 598 amino acids, but parts of loops 1 (residues 340–363), 3 (residues 408–417), 4 (residues 454–471), 5 (residues 533–542), and 6 (residues 576–606) are missing in the model. This is in the reference for the crystallization of the model. Review the amino acid numbering; for example, gamma-carotene lists AL742, and cis-beta-carotene lists LA482 and RG483, alpha-carotene lists RP797, which are incorrect. Page 16 : The section "(BBB - permeability = YES or > 0.1); (GI - absorption = high); (Carcinogenicity = 0 to 0.3); (PAINS alert = 0) and (Lipinski’s violation = 0)" is disjointed from the text. Integrate it into the following paragraph, mentioning that these are the reference values for these variables. These would be my recommendations. Competing Interests: No competing interests were disclosed. Reviewer Expertise: virology, antiviral design, rational drug design, and enzyme kinetics, molecular biology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Marquez-Dominguez L. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.168075.r295619 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v2#referee-response-295619 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Vijaya Anand A. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.168075.r295618 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v2#referee-response-295618 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 17 Jul 2024 Arumugam Vijaya Anand , Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.168075.r295618 1. This suggestion is not properly carried out and it should be rectified. The use of abbreviations in the abstract ... Continue reading READ ALL 1. This suggestion is not properly carried out and it should be rectified. The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Phytotherapeuics, Clinical Biochemistry, Medical Genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Vijaya Anand A. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.168075.r295618 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v2#referee-response-295618 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 13 Jun 2023 Views 0 Cite How to cite this report: Singh TR. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r273118 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-273118 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 10 Sep 2024 Tiratha Raj Singh , Jaypee University of Information Technology (JUIT), Himachal Pradesh, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.148054.r273118 The article titled " In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein" by Kumaree et al is an interesting piece of work where authors have utilized in details all the structural bioinformatics components to analyze ... Continue reading READ ALL The article titled " In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein" by Kumaree et al is an interesting piece of work where authors have utilized in details all the structural bioinformatics components to analyze and annotate data utilized for the design of novel inhibitors for Zika virus protein. They also proposed that their studies results will be confirmed if experimental validations could be done in future. There are some typos and minor grammar issues along with the abbreviations used in the manuscript. Authors are suggested to rectify all these issues. There is no separate conclusion added, it should be added with specific outcomes of the study. Use of either “ZIKA” or “Zika” all over the manuscript be a better idea for making it uniform? Are there any other phytocompounds in the mentioned plant, which could be used for further studies.As the used compounds are naturally available, are their IC50 values available. If yes authors may compile this information for the readers, will add value to the research. There are some good articles such as: [ ref 1 ], which can also help the authors to look for technical contents for the refinements of the overall process. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Shukla R, Chandra A, Kumar A, Kandpal P, et al.: Repurposing of drugs against methyltransferase as potential Zika virus therapies. Sci Rep . 2023; 13 (1): 7870 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Bioinformatics and Systems Biology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Singh TR. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r273118 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-273118 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Marquez-Dominguez L. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r228783 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-228783 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 May 2024 Luis Marquez-Dominguez , Instituto Mexicano del Seguro Social, Puebla, Mexico Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.148054.r228783 The quest for compounds exhibiting antiviral activity against diseases such as Zika is of paramount importance, given the absence of a definitive treatment for this ailment. However, I have several suggestions and reservations regarding the manuscript's content. Among the significant ... Continue reading READ ALL The quest for compounds exhibiting antiviral activity against diseases such as Zika is of paramount importance, given the absence of a definitive treatment for this ailment. However, I have several suggestions and reservations regarding the manuscript's content. Among the significant revisions required, it is observed that one of the receptors does not correspond to the Zika virus. Until the authors clarify this discrepancy, the integrity of the results, discussion, conclusions remains questionable. 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus diagram, rather than just a segment of it. 2. Concerning the selection of receptors, the NS5 RdRp with PDB key 5UO4 corresponds to the Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)ethyl) benzonitrile, and not to the NS5 RdRp of the Zika virus. This discrepancy is also evident in the supplementary data. Was all docking and figure rendering performed using the 5UO4 structure, which does not represent the Zika NS5 RdRp? If so, a substantial portion of the results may not be reflective. I recommend a thorough verification. When compared with NS5 RdRp structures with PDB codes 5Wz3 or 5U0B, there appears to be no similarity. 3. The methodology mentions obtaining 9 coupling results, yet it fails to specify the criteria used to select the optimal molecular coupling model. Please provide clarity on the selection process. 4. In the section on "Ligand and receptor molecular docking," the size of the grid is redundantly stated. 5. In the "Result Molecular Docking" section, the references for the positive ligands (controls) do not support their selection. For example, concerning sinefungin, it is mentioned that they were designed by HVC, but there is no information related to flavivirus or Zika. The same applies to sofosbuvir. I suggest modifying the references to accurately reflect their relevance. 6. The images exhibit low resolution, hindering effective structure visualization. Therefore, I recommend enhancing clarity for better interpretation. Specifically, in Figure 4, the sharpness is insufficient for clear visualization of 2D diagrams, and the residues interacting with molecules are not distinguishable from the representation of alpha helices and beta sheets. The legend of interactions is unreadable, and the figure caption lacks information on the meaning of each color. For improved comparison, I suggest including controls (sofosbuvir and sinefungin) in Figure 4. Additionally, consider incorporating a surface representation with electrostatic charges to highlight hydrophobic regions or regions with electrostatic charges interacting with molecules. 7. In Figure 3, in the 5UO4 table, the control -7.40 should be white as it serves as the reference. It appears blue, possibly due to incorrectly taking the positive ligand of 5WXB as a reference. This is inaccurate, as it is a receptor and a distinct molecule. 8. Table 1 in the docking results mentions different types of non-covalent interactions without justifying why only hydrogen bond bonds and hydrophobic interactions were considered. The discussion also lacks insights into the differences or importance of various interactions such as alkyl-alkyl, pi-alkyl, etc. I recommend ordering the amino acids in ascending order for clarity. 9. In the discussion of interactions between molecules (rutin) versus sofosbuvir, there is mention of a greater number of interactions, but the explanation on how these interactions lead to blocking the active site is lacking. Consider discussing whether this blocking results from size or other characteristics inherent to enzymatic activity inhibition. A more in-depth discussion of the results is suggested. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Not applicable Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly References 1. Noreen, Ali R, Badshah SL, Faheem M, et al.: Identification of potential inhibitors of Zika virus NS5 RNA-dependent RNA polymerase through virtual screening and molecular dynamic simulations. Saudi Pharm J . 2020; 28 (12): 1580-1591 PubMed Abstract | Publisher Full Text 2. Lim SP, Noble CG, Shi PY: The dengue virus NS5 protein as a target for drug discovery. Antiviral Res . 2015; 119 : 57-67 PubMed Abstract | Publisher Full Text 3. Song W, Zhang H, Zhang Y, Chen Y, et al.: Identification and Characterization of Zika Virus NS5 Methyltransferase Inhibitors. Front Cell Infect Microbiol . 2021; 11 : 665379 PubMed Abstract | Publisher Full Text 4. Ramharack P, Soliman MES: Zika virus NS5 protein potential inhibitors: an enhanced in silico approach in drug discovery. J Biomol Struct Dyn . 2018; 36 (5): 1118-1133 PubMed Abstract | Publisher Full Text 5. Nascimento IJDS, Santos-Júnior PFDS, Aquino TM, Araújo-Júnior JX, et al.: Insights on Dengue and Zika NS5 RNA-dependent RNA polymerase (RdRp) inhibitors. Eur J Med Chem . 2021; 224 : 113698 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: virology, antiviral design, rational drug design, and enzyme kinetics, molecular biology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Marquez-Dominguez L. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r228783 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-228783 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 25 Jun 2024 kishore krishna kumaree , Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 25 Jun 2024 Author Response 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus ... Continue reading 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus diagram, rather than just a segment of it. Answer: Thank you for your suggestion, We have replaced the figure 1 with a new figure in the manuscript. 2. Concerning the selection of receptors, the NS5 RdRp with PDB key 5UO4 corresponds to the Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)ethyl) benzonitrile, and not to the NS5 RdRp of the Zika virus. This discrepancy is also evident in the supplementary data. Was all docking and figure rendering performed using the 5UO4 structure, which does not represent the Zika NS5 RdRp? If so, a substantial portion of the results may not be reflective. I recommend a thorough verification. When compared with NS5 RdRp structures with PDB codes 5Wz3 or 5U0B, there appears to be no similarity. Answer: Thank you for your meticulous review and valuable feedback. I sincerely apologize for the oversight regarding the receptor used in our study. There was indeed a typographical error in the manuscript. The correct PDB code for the Zika virus NS5 RdRp that we used for our analyses is 5U04, not 5UO4. I assure you that all docking and technical analyses were conducted using the 5U04 structure, which accurately represents the Zika NS5 RdRp. The incorrect PDB code in the text was an unfortunate typographical mistake, and we will promptly correct this in the manuscript and the supplementary data to reflect the accurate PDB code. We greatly appreciate your diligence in pointing out this discrepancy and apologize for any confusion it may have caused. Your feedback is crucial for maintaining the integrity of our work, and we will ensure that such errors are rectified to convey our research findings accurately. 3. The methodology mentions obtaining 9 coupling results, yet it fails to specify the criteria used to select the optimal molecular coupling model. Please provide clarity on the selection process. Answer: The selection of the optimal molecular model was done based on the lower binding energy (more negative value), a higher number of hydrogen bonds, and other nonbonded interactions, including hydrophobic and electrostatic interactions. In addition, conserved binding pocket interactions were also considered and compared with the known control inhibitors for the respective target proteins.We believe this multifaceted approach provides a more robust optimal model selection. 4. In the section on "Ligand and receptor molecular docking," the size of the grid is redundantly stated. Answer: The redundancy mentioning of grid size has been corrected in the revised manuscript. 5. In the "Result Molecular Docking" section, the references for the positive ligands (controls) do not support their selection. For example, concerning sinefungin, it is mentioned that they were designed by HVC, but there is no information related to flavivirus or Zika. The same applies to sofosbuvir. I suggest modifying the references to accurately reflect their relevance. Answer: Thank you for your careful review and for highlighting the need to ensure the references for our positive control ligands are accurate and relevant. We apologize for any oversight in the current references and appreciate your suggestion to provide more relevant citations. In response to your concern and to support our selection, we have updated the manuscript and have included the following references: Sinefungin and Sofosbuvir were the reference inhibitors for NS5-MTase and NS5 RdRp, respectively. References: Hercik, K., et al., Structural basis of Zika virus methyltransferase inhibition by sinefungin. Archives of virology, 2017. 162 : p. 2091-2096. Lin, Y., et al., Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors. International journal of antimicrobial agents, 2019. 54 (4): p. 502-506. Sacramento, C.Q., et al., The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Scientific reports, 2017. 7 (1): p. 40920. Tao, Z., et al., Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives. European Journal of Medicinal Chemistry, 2018. 157 : p. 994-1004. 6. The images exhibit low resolution, hindering effective structure visualization. Therefore, I recommend enhancing clarity for better interpretation. Specifically, in Figure 4, the sharpness is insufficient for clear visualization of 2D diagrams, and the residues interacting with molecules are not distinguishable from the representation of alpha helices and beta sheets. The legend of interactions is unreadable, and the figure caption lacks information on the meaning of each color. For improved comparison, I suggest including controls (sofosbuvir and sinefungin) in Figure 4. Additionally, consider incorporating a surface representation with electrostatic charges to highlight hydrophobic regions or regions with electrostatic charges interacting with molecules. Answer: Thank you for your constructive feedback regarding the visualization quality of the images in Figure 4. We have considered your recommendations and replaced the images with higher-resolution versions to enhance clarity and facilitate better interpretation. However, at this stage, we have not incorporated surface representations with electrostatic charges to highlight hydrophobic regions and regions with electrostatic interactions. We will consider including these enhancements in future revisions to improve the visualization quality further. Additionally, we have included controls (sofosbuvir and sinefungin) in Figure 4 for improved comparison. We appreciate your valuable feedback, which has significantly improved the quality and clarity of our manuscript. Thank you for your continued support in refining our research. 7. In Figure 3, in the 5UO4 table, the control -7.40 should be white as it serves as the reference. It appears blue, possibly due to incorrectly taking the positive ligand of 5WXB as a reference. This is inaccurate, as it is a receptor and a distinct molecule. Answer: Thank you for pointing out the issue with the color assignment in Figure 3. We have redone the color mapping for the complexes 5U04 and 5WXB table in Figure 3. The new figure has been added to the manuscript. 8. Table 1 in the docking results mentions different types of non-covalent interactions without justifying why only hydrogen bond bonds and hydrophobic interactions were considered. The discussion also lacks insights into the differences or importance of various interactions such as alkyl-alkyl, pi-alkyl, etc. I recommend ordering the amino acids in ascending order for clarity. Answer: Thank you for your insightful feedback regarding the non-covalent interactions mentioned in Table 1 of the docking results. In our study, we focused on hydrogen bonds and hydrophobic interactions due to their significant roles in stabilizing ligand binding within the receptor's active site. Hydrogen bonds are essential for providing specificity and strong directional interactions, while hydrophobic interactions contribute to binding affinity by facilitating the burial of non-polar surfaces and reducing desolvation penalties. Although other non-covalent interactions such as alkyl-alkyl, pi-alkyl, and pi-pi interactions also play important roles in ligand-receptor binding, we prioritized hydrogen bonds and hydrophobic interactions due to their dominant influence in many docking studies. We have also included an explanation in the manuscript's discussion section. Furthermore, we have arranged the amino acids in Table 1 in their chronological order of occurrence within the protein sequence and structure, reflecting the sequential interaction pattern and spatial context, which is crucial for understanding the binding interactions. This arrangement aids in visualizing the interactions as they occur along the protein's active site and aligns with standard conventions in protein interaction studies. 9. In the discussion of interactions between molecules (rutin) versus sofosbuvir, there is mention of a greater number of interactions, but the explanation on how these interactions lead to blocking the active site is lacking. Consider discussing whether this blocking results from size or other characteristics inherent to enzymatic activity inhibition. A more in-depth discussion of the results is suggested. Answer: Thank you for your valuable feedback and suggestion for a more in-depth discussion of the interactions between rutin and sofosbuvir To address the interactions between rutin and sofosbuvir with the active site, we provide a more detailed discussion on how these interactions contribute to the inhibition of enzymatic activity. Rutin exhibits a greater number of interactions compared to sofosbuvir, which enhances its ability to effectively block the active site. This blocking is not solely a function of the number of interactions but also their nature and strength. The larger size of rutin allows it to span a broader area of the active site, facilitating multiple points of contact through hydrogen bonds, hydrophobic interactions, and aromatic stacking. These interactions collectively stabilize the binding of rutin within the active site, thereby preventing substrate access and subsequent enzymatic activity. In contrast, while sofosbuvir also forms stable interactions, the fewer number and potentially weaker nature of these interactions may result in less effective blocking. Thus, rutin's increased binding affinity and comprehensive interaction profile contribute to its potential as a more effective inhibitor of the enzyme's active site. 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus diagram, rather than just a segment of it. Answer: Thank you for your suggestion, We have replaced the figure 1 with a new figure in the manuscript. 2. Concerning the selection of receptors, the NS5 RdRp with PDB key 5UO4 corresponds to the Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)ethyl) benzonitrile, and not to the NS5 RdRp of the Zika virus. This discrepancy is also evident in the supplementary data. Was all docking and figure rendering performed using the 5UO4 structure, which does not represent the Zika NS5 RdRp? If so, a substantial portion of the results may not be reflective. I recommend a thorough verification. When compared with NS5 RdRp structures with PDB codes 5Wz3 or 5U0B, there appears to be no similarity. Answer: Thank you for your meticulous review and valuable feedback. I sincerely apologize for the oversight regarding the receptor used in our study. There was indeed a typographical error in the manuscript. The correct PDB code for the Zika virus NS5 RdRp that we used for our analyses is 5U04, not 5UO4. I assure you that all docking and technical analyses were conducted using the 5U04 structure, which accurately represents the Zika NS5 RdRp. The incorrect PDB code in the text was an unfortunate typographical mistake, and we will promptly correct this in the manuscript and the supplementary data to reflect the accurate PDB code. We greatly appreciate your diligence in pointing out this discrepancy and apologize for any confusion it may have caused. Your feedback is crucial for maintaining the integrity of our work, and we will ensure that such errors are rectified to convey our research findings accurately. 3. The methodology mentions obtaining 9 coupling results, yet it fails to specify the criteria used to select the optimal molecular coupling model. Please provide clarity on the selection process. Answer: The selection of the optimal molecular model was done based on the lower binding energy (more negative value), a higher number of hydrogen bonds, and other nonbonded interactions, including hydrophobic and electrostatic interactions. In addition, conserved binding pocket interactions were also considered and compared with the known control inhibitors for the respective target proteins.We believe this multifaceted approach provides a more robust optimal model selection. 4. In the section on "Ligand and receptor molecular docking," the size of the grid is redundantly stated. Answer: The redundancy mentioning of grid size has been corrected in the revised manuscript. 5. In the "Result Molecular Docking" section, the references for the positive ligands (controls) do not support their selection. For example, concerning sinefungin, it is mentioned that they were designed by HVC, but there is no information related to flavivirus or Zika. The same applies to sofosbuvir. I suggest modifying the references to accurately reflect their relevance. Answer: Thank you for your careful review and for highlighting the need to ensure the references for our positive control ligands are accurate and relevant. We apologize for any oversight in the current references and appreciate your suggestion to provide more relevant citations. In response to your concern and to support our selection, we have updated the manuscript and have included the following references: Sinefungin and Sofosbuvir were the reference inhibitors for NS5-MTase and NS5 RdRp, respectively. References: Hercik, K., et al., Structural basis of Zika virus methyltransferase inhibition by sinefungin. Archives of virology, 2017. 162 : p. 2091-2096. Lin, Y., et al., Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors. International journal of antimicrobial agents, 2019. 54 (4): p. 502-506. Sacramento, C.Q., et al., The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Scientific reports, 2017. 7 (1): p. 40920. Tao, Z., et al., Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives. European Journal of Medicinal Chemistry, 2018. 157 : p. 994-1004. 6. The images exhibit low resolution, hindering effective structure visualization. Therefore, I recommend enhancing clarity for better interpretation. Specifically, in Figure 4, the sharpness is insufficient for clear visualization of 2D diagrams, and the residues interacting with molecules are not distinguishable from the representation of alpha helices and beta sheets. The legend of interactions is unreadable, and the figure caption lacks information on the meaning of each color. For improved comparison, I suggest including controls (sofosbuvir and sinefungin) in Figure 4. Additionally, consider incorporating a surface representation with electrostatic charges to highlight hydrophobic regions or regions with electrostatic charges interacting with molecules. Answer: Thank you for your constructive feedback regarding the visualization quality of the images in Figure 4. We have considered your recommendations and replaced the images with higher-resolution versions to enhance clarity and facilitate better interpretation. However, at this stage, we have not incorporated surface representations with electrostatic charges to highlight hydrophobic regions and regions with electrostatic interactions. We will consider including these enhancements in future revisions to improve the visualization quality further. Additionally, we have included controls (sofosbuvir and sinefungin) in Figure 4 for improved comparison. We appreciate your valuable feedback, which has significantly improved the quality and clarity of our manuscript. Thank you for your continued support in refining our research. 7. In Figure 3, in the 5UO4 table, the control -7.40 should be white as it serves as the reference. It appears blue, possibly due to incorrectly taking the positive ligand of 5WXB as a reference. This is inaccurate, as it is a receptor and a distinct molecule. Answer: Thank you for pointing out the issue with the color assignment in Figure 3. We have redone the color mapping for the complexes 5U04 and 5WXB table in Figure 3. The new figure has been added to the manuscript. 8. Table 1 in the docking results mentions different types of non-covalent interactions without justifying why only hydrogen bond bonds and hydrophobic interactions were considered. The discussion also lacks insights into the differences or importance of various interactions such as alkyl-alkyl, pi-alkyl, etc. I recommend ordering the amino acids in ascending order for clarity. Answer: Thank you for your insightful feedback regarding the non-covalent interactions mentioned in Table 1 of the docking results. In our study, we focused on hydrogen bonds and hydrophobic interactions due to their significant roles in stabilizing ligand binding within the receptor's active site. Hydrogen bonds are essential for providing specificity and strong directional interactions, while hydrophobic interactions contribute to binding affinity by facilitating the burial of non-polar surfaces and reducing desolvation penalties. Although other non-covalent interactions such as alkyl-alkyl, pi-alkyl, and pi-pi interactions also play important roles in ligand-receptor binding, we prioritized hydrogen bonds and hydrophobic interactions due to their dominant influence in many docking studies. We have also included an explanation in the manuscript's discussion section. Furthermore, we have arranged the amino acids in Table 1 in their chronological order of occurrence within the protein sequence and structure, reflecting the sequential interaction pattern and spatial context, which is crucial for understanding the binding interactions. This arrangement aids in visualizing the interactions as they occur along the protein's active site and aligns with standard conventions in protein interaction studies. 9. In the discussion of interactions between molecules (rutin) versus sofosbuvir, there is mention of a greater number of interactions, but the explanation on how these interactions lead to blocking the active site is lacking. Consider discussing whether this blocking results from size or other characteristics inherent to enzymatic activity inhibition. A more in-depth discussion of the results is suggested. Answer: Thank you for your valuable feedback and suggestion for a more in-depth discussion of the interactions between rutin and sofosbuvir To address the interactions between rutin and sofosbuvir with the active site, we provide a more detailed discussion on how these interactions contribute to the inhibition of enzymatic activity. Rutin exhibits a greater number of interactions compared to sofosbuvir, which enhances its ability to effectively block the active site. This blocking is not solely a function of the number of interactions but also their nature and strength. The larger size of rutin allows it to span a broader area of the active site, facilitating multiple points of contact through hydrogen bonds, hydrophobic interactions, and aromatic stacking. These interactions collectively stabilize the binding of rutin within the active site, thereby preventing substrate access and subsequent enzymatic activity. In contrast, while sofosbuvir also forms stable interactions, the fewer number and potentially weaker nature of these interactions may result in less effective blocking. Thus, rutin's increased binding affinity and comprehensive interaction profile contribute to its potential as a more effective inhibitor of the enzyme's active site. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 25 Jun 2024 kishore krishna kumaree , Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 25 Jun 2024 Author Response 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus ... Continue reading 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus diagram, rather than just a segment of it. Answer: Thank you for your suggestion, We have replaced the figure 1 with a new figure in the manuscript. 2. Concerning the selection of receptors, the NS5 RdRp with PDB key 5UO4 corresponds to the Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)ethyl) benzonitrile, and not to the NS5 RdRp of the Zika virus. This discrepancy is also evident in the supplementary data. Was all docking and figure rendering performed using the 5UO4 structure, which does not represent the Zika NS5 RdRp? If so, a substantial portion of the results may not be reflective. I recommend a thorough verification. When compared with NS5 RdRp structures with PDB codes 5Wz3 or 5U0B, there appears to be no similarity. Answer: Thank you for your meticulous review and valuable feedback. I sincerely apologize for the oversight regarding the receptor used in our study. There was indeed a typographical error in the manuscript. The correct PDB code for the Zika virus NS5 RdRp that we used for our analyses is 5U04, not 5UO4. I assure you that all docking and technical analyses were conducted using the 5U04 structure, which accurately represents the Zika NS5 RdRp. The incorrect PDB code in the text was an unfortunate typographical mistake, and we will promptly correct this in the manuscript and the supplementary data to reflect the accurate PDB code. We greatly appreciate your diligence in pointing out this discrepancy and apologize for any confusion it may have caused. Your feedback is crucial for maintaining the integrity of our work, and we will ensure that such errors are rectified to convey our research findings accurately. 3. The methodology mentions obtaining 9 coupling results, yet it fails to specify the criteria used to select the optimal molecular coupling model. Please provide clarity on the selection process. Answer: The selection of the optimal molecular model was done based on the lower binding energy (more negative value), a higher number of hydrogen bonds, and other nonbonded interactions, including hydrophobic and electrostatic interactions. In addition, conserved binding pocket interactions were also considered and compared with the known control inhibitors for the respective target proteins.We believe this multifaceted approach provides a more robust optimal model selection. 4. In the section on "Ligand and receptor molecular docking," the size of the grid is redundantly stated. Answer: The redundancy mentioning of grid size has been corrected in the revised manuscript. 5. In the "Result Molecular Docking" section, the references for the positive ligands (controls) do not support their selection. For example, concerning sinefungin, it is mentioned that they were designed by HVC, but there is no information related to flavivirus or Zika. The same applies to sofosbuvir. I suggest modifying the references to accurately reflect their relevance. Answer: Thank you for your careful review and for highlighting the need to ensure the references for our positive control ligands are accurate and relevant. We apologize for any oversight in the current references and appreciate your suggestion to provide more relevant citations. In response to your concern and to support our selection, we have updated the manuscript and have included the following references: Sinefungin and Sofosbuvir were the reference inhibitors for NS5-MTase and NS5 RdRp, respectively. References: Hercik, K., et al., Structural basis of Zika virus methyltransferase inhibition by sinefungin. Archives of virology, 2017. 162 : p. 2091-2096. Lin, Y., et al., Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors. International journal of antimicrobial agents, 2019. 54 (4): p. 502-506. Sacramento, C.Q., et al., The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Scientific reports, 2017. 7 (1): p. 40920. Tao, Z., et al., Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives. European Journal of Medicinal Chemistry, 2018. 157 : p. 994-1004. 6. The images exhibit low resolution, hindering effective structure visualization. Therefore, I recommend enhancing clarity for better interpretation. Specifically, in Figure 4, the sharpness is insufficient for clear visualization of 2D diagrams, and the residues interacting with molecules are not distinguishable from the representation of alpha helices and beta sheets. The legend of interactions is unreadable, and the figure caption lacks information on the meaning of each color. For improved comparison, I suggest including controls (sofosbuvir and sinefungin) in Figure 4. Additionally, consider incorporating a surface representation with electrostatic charges to highlight hydrophobic regions or regions with electrostatic charges interacting with molecules. Answer: Thank you for your constructive feedback regarding the visualization quality of the images in Figure 4. We have considered your recommendations and replaced the images with higher-resolution versions to enhance clarity and facilitate better interpretation. However, at this stage, we have not incorporated surface representations with electrostatic charges to highlight hydrophobic regions and regions with electrostatic interactions. We will consider including these enhancements in future revisions to improve the visualization quality further. Additionally, we have included controls (sofosbuvir and sinefungin) in Figure 4 for improved comparison. We appreciate your valuable feedback, which has significantly improved the quality and clarity of our manuscript. Thank you for your continued support in refining our research. 7. In Figure 3, in the 5UO4 table, the control -7.40 should be white as it serves as the reference. It appears blue, possibly due to incorrectly taking the positive ligand of 5WXB as a reference. This is inaccurate, as it is a receptor and a distinct molecule. Answer: Thank you for pointing out the issue with the color assignment in Figure 3. We have redone the color mapping for the complexes 5U04 and 5WXB table in Figure 3. The new figure has been added to the manuscript. 8. Table 1 in the docking results mentions different types of non-covalent interactions without justifying why only hydrogen bond bonds and hydrophobic interactions were considered. The discussion also lacks insights into the differences or importance of various interactions such as alkyl-alkyl, pi-alkyl, etc. I recommend ordering the amino acids in ascending order for clarity. Answer: Thank you for your insightful feedback regarding the non-covalent interactions mentioned in Table 1 of the docking results. In our study, we focused on hydrogen bonds and hydrophobic interactions due to their significant roles in stabilizing ligand binding within the receptor's active site. Hydrogen bonds are essential for providing specificity and strong directional interactions, while hydrophobic interactions contribute to binding affinity by facilitating the burial of non-polar surfaces and reducing desolvation penalties. Although other non-covalent interactions such as alkyl-alkyl, pi-alkyl, and pi-pi interactions also play important roles in ligand-receptor binding, we prioritized hydrogen bonds and hydrophobic interactions due to their dominant influence in many docking studies. We have also included an explanation in the manuscript's discussion section. Furthermore, we have arranged the amino acids in Table 1 in their chronological order of occurrence within the protein sequence and structure, reflecting the sequential interaction pattern and spatial context, which is crucial for understanding the binding interactions. This arrangement aids in visualizing the interactions as they occur along the protein's active site and aligns with standard conventions in protein interaction studies. 9. In the discussion of interactions between molecules (rutin) versus sofosbuvir, there is mention of a greater number of interactions, but the explanation on how these interactions lead to blocking the active site is lacking. Consider discussing whether this blocking results from size or other characteristics inherent to enzymatic activity inhibition. A more in-depth discussion of the results is suggested. Answer: Thank you for your valuable feedback and suggestion for a more in-depth discussion of the interactions between rutin and sofosbuvir To address the interactions between rutin and sofosbuvir with the active site, we provide a more detailed discussion on how these interactions contribute to the inhibition of enzymatic activity. Rutin exhibits a greater number of interactions compared to sofosbuvir, which enhances its ability to effectively block the active site. This blocking is not solely a function of the number of interactions but also their nature and strength. The larger size of rutin allows it to span a broader area of the active site, facilitating multiple points of contact through hydrogen bonds, hydrophobic interactions, and aromatic stacking. These interactions collectively stabilize the binding of rutin within the active site, thereby preventing substrate access and subsequent enzymatic activity. In contrast, while sofosbuvir also forms stable interactions, the fewer number and potentially weaker nature of these interactions may result in less effective blocking. Thus, rutin's increased binding affinity and comprehensive interaction profile contribute to its potential as a more effective inhibitor of the enzyme's active site. 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus diagram, rather than just a segment of it. Answer: Thank you for your suggestion, We have replaced the figure 1 with a new figure in the manuscript. 2. Concerning the selection of receptors, the NS5 RdRp with PDB key 5UO4 corresponds to the Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)ethyl) benzonitrile, and not to the NS5 RdRp of the Zika virus. This discrepancy is also evident in the supplementary data. Was all docking and figure rendering performed using the 5UO4 structure, which does not represent the Zika NS5 RdRp? If so, a substantial portion of the results may not be reflective. I recommend a thorough verification. When compared with NS5 RdRp structures with PDB codes 5Wz3 or 5U0B, there appears to be no similarity. Answer: Thank you for your meticulous review and valuable feedback. I sincerely apologize for the oversight regarding the receptor used in our study. There was indeed a typographical error in the manuscript. The correct PDB code for the Zika virus NS5 RdRp that we used for our analyses is 5U04, not 5UO4. I assure you that all docking and technical analyses were conducted using the 5U04 structure, which accurately represents the Zika NS5 RdRp. The incorrect PDB code in the text was an unfortunate typographical mistake, and we will promptly correct this in the manuscript and the supplementary data to reflect the accurate PDB code. We greatly appreciate your diligence in pointing out this discrepancy and apologize for any confusion it may have caused. Your feedback is crucial for maintaining the integrity of our work, and we will ensure that such errors are rectified to convey our research findings accurately. 3. The methodology mentions obtaining 9 coupling results, yet it fails to specify the criteria used to select the optimal molecular coupling model. Please provide clarity on the selection process. Answer: The selection of the optimal molecular model was done based on the lower binding energy (more negative value), a higher number of hydrogen bonds, and other nonbonded interactions, including hydrophobic and electrostatic interactions. In addition, conserved binding pocket interactions were also considered and compared with the known control inhibitors for the respective target proteins.We believe this multifaceted approach provides a more robust optimal model selection. 4. In the section on "Ligand and receptor molecular docking," the size of the grid is redundantly stated. Answer: The redundancy mentioning of grid size has been corrected in the revised manuscript. 5. In the "Result Molecular Docking" section, the references for the positive ligands (controls) do not support their selection. For example, concerning sinefungin, it is mentioned that they were designed by HVC, but there is no information related to flavivirus or Zika. The same applies to sofosbuvir. I suggest modifying the references to accurately reflect their relevance. Answer: Thank you for your careful review and for highlighting the need to ensure the references for our positive control ligands are accurate and relevant. We apologize for any oversight in the current references and appreciate your suggestion to provide more relevant citations. In response to your concern and to support our selection, we have updated the manuscript and have included the following references: Sinefungin and Sofosbuvir were the reference inhibitors for NS5-MTase and NS5 RdRp, respectively. References: Hercik, K., et al., Structural basis of Zika virus methyltransferase inhibition by sinefungin. Archives of virology, 2017. 162 : p. 2091-2096. Lin, Y., et al., Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors. International journal of antimicrobial agents, 2019. 54 (4): p. 502-506. Sacramento, C.Q., et al., The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Scientific reports, 2017. 7 (1): p. 40920. Tao, Z., et al., Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives. European Journal of Medicinal Chemistry, 2018. 157 : p. 994-1004. 6. The images exhibit low resolution, hindering effective structure visualization. Therefore, I recommend enhancing clarity for better interpretation. Specifically, in Figure 4, the sharpness is insufficient for clear visualization of 2D diagrams, and the residues interacting with molecules are not distinguishable from the representation of alpha helices and beta sheets. The legend of interactions is unreadable, and the figure caption lacks information on the meaning of each color. For improved comparison, I suggest including controls (sofosbuvir and sinefungin) in Figure 4. Additionally, consider incorporating a surface representation with electrostatic charges to highlight hydrophobic regions or regions with electrostatic charges interacting with molecules. Answer: Thank you for your constructive feedback regarding the visualization quality of the images in Figure 4. We have considered your recommendations and replaced the images with higher-resolution versions to enhance clarity and facilitate better interpretation. However, at this stage, we have not incorporated surface representations with electrostatic charges to highlight hydrophobic regions and regions with electrostatic interactions. We will consider including these enhancements in future revisions to improve the visualization quality further. Additionally, we have included controls (sofosbuvir and sinefungin) in Figure 4 for improved comparison. We appreciate your valuable feedback, which has significantly improved the quality and clarity of our manuscript. Thank you for your continued support in refining our research. 7. In Figure 3, in the 5UO4 table, the control -7.40 should be white as it serves as the reference. It appears blue, possibly due to incorrectly taking the positive ligand of 5WXB as a reference. This is inaccurate, as it is a receptor and a distinct molecule. Answer: Thank you for pointing out the issue with the color assignment in Figure 3. We have redone the color mapping for the complexes 5U04 and 5WXB table in Figure 3. The new figure has been added to the manuscript. 8. Table 1 in the docking results mentions different types of non-covalent interactions without justifying why only hydrogen bond bonds and hydrophobic interactions were considered. The discussion also lacks insights into the differences or importance of various interactions such as alkyl-alkyl, pi-alkyl, etc. I recommend ordering the amino acids in ascending order for clarity. Answer: Thank you for your insightful feedback regarding the non-covalent interactions mentioned in Table 1 of the docking results. In our study, we focused on hydrogen bonds and hydrophobic interactions due to their significant roles in stabilizing ligand binding within the receptor's active site. Hydrogen bonds are essential for providing specificity and strong directional interactions, while hydrophobic interactions contribute to binding affinity by facilitating the burial of non-polar surfaces and reducing desolvation penalties. Although other non-covalent interactions such as alkyl-alkyl, pi-alkyl, and pi-pi interactions also play important roles in ligand-receptor binding, we prioritized hydrogen bonds and hydrophobic interactions due to their dominant influence in many docking studies. We have also included an explanation in the manuscript's discussion section. Furthermore, we have arranged the amino acids in Table 1 in their chronological order of occurrence within the protein sequence and structure, reflecting the sequential interaction pattern and spatial context, which is crucial for understanding the binding interactions. This arrangement aids in visualizing the interactions as they occur along the protein's active site and aligns with standard conventions in protein interaction studies. 9. In the discussion of interactions between molecules (rutin) versus sofosbuvir, there is mention of a greater number of interactions, but the explanation on how these interactions lead to blocking the active site is lacking. Consider discussing whether this blocking results from size or other characteristics inherent to enzymatic activity inhibition. A more in-depth discussion of the results is suggested. Answer: Thank you for your valuable feedback and suggestion for a more in-depth discussion of the interactions between rutin and sofosbuvir To address the interactions between rutin and sofosbuvir with the active site, we provide a more detailed discussion on how these interactions contribute to the inhibition of enzymatic activity. Rutin exhibits a greater number of interactions compared to sofosbuvir, which enhances its ability to effectively block the active site. This blocking is not solely a function of the number of interactions but also their nature and strength. The larger size of rutin allows it to span a broader area of the active site, facilitating multiple points of contact through hydrogen bonds, hydrophobic interactions, and aromatic stacking. These interactions collectively stabilize the binding of rutin within the active site, thereby preventing substrate access and subsequent enzymatic activity. In contrast, while sofosbuvir also forms stable interactions, the fewer number and potentially weaker nature of these interactions may result in less effective blocking. Thus, rutin's increased binding affinity and comprehensive interaction profile contribute to its potential as a more effective inhibitor of the enzyme's active site. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Vijaya Anand A. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r214337 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-214337 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 18 Oct 2023 Arumugam Vijaya Anand , Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.148054.r214337 The authors have put effort to evaluate the “ In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5”. The authors describe the research undertaken with this in an organized manner, emphasizing the results obtained ... Continue reading READ ALL The authors have put effort to evaluate the “ In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5”. The authors describe the research undertaken with this in an organized manner, emphasizing the results obtained by them. The article needs modification for better cohesion of information to achieve the goal and the shortcomings which need to be considered. Hence, the paper can be approved after MAJOR REVISIONS are carried out. 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words “subjected for” may be as “subjected to”; “NS5-MTase” as “the NS5-MTase”; “by ADMET” as “by an ADMET”; “addition of” as “the addition of”; “removal of” as “the removal of”; “ranging 0.111” as “ranging from 0.111”; “zeaxanthin” as “and zeaxanthin”. The grammar mistakes which are not mentioned here are also to be checked and corrected properly. 2. There are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words “encode a” may be as “encodes a”; “decent” as “descent”; “Ligands” as “Ligand”; “best docked” as “best-docked”; “nor vaccines” as “no vaccines”; “other site” as “other side”; “rutin, has” as “rutin has”; “β-sitsterol” as “β-sitosterol or check correct spelling”; “caretenoids” as “carotenoids”. The typos not mentioned here are also to be checked and corrected properly. 3. Check the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the abstract (The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full) and the remaining part of the manuscript (For example, PDP, FDA, etc.,). Make a word abbreviated in the article that is repeated at least three times in the text, not all words to be abbreviated. 4. The full form of the species should be given when the first time appears in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Carica papaya when the first time appear and followed by C. papaya ). 5. The authors should use uniformly either “ZIKA” or “Zika” all over the manuscript for better understanding. 6. The authors may cite recent prevalence or incidence data Zika virus (ZIKV) infection and it should be at-least of 2022 or 2023. 7. The introduction part appears less informative about Carica papaya , thus this section should be indicated as detailed to understand the manuscript in clear since the main objectives is focused on Carica papaya . The botanical description, family name and different plants of the plant with it medicinal uses. 8. The authors should rewrite the following “The paper aims” as “The present work or study aims”. 9. The authors should avoid the repetition some content in the manuscript and also it affect the flow of reading. It should be carefully checked and removed. For example, the family name “Flaviviridae” of ZIKA has been mentioned in three times. 10. The conclusion seems in general. All conclusions must be convincing statements on what was found to be novel, impact based on the strong support of the review. Moreover, the authors may also be included the limitation of the present findings for a better understanding of the manuscript. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Not applicable Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Phytotherapeuics, Clinical Biochemistry, Medical Genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Vijaya Anand A. Reviewer Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r214337 ) The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-214337 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 25 Jun 2024 kishore krishna kumaree , Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 25 Jun 2024 Author Response 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words "subjected for" may be as "subjected to"; "NS5-MTase" as "the ... Continue reading 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words "subjected for" may be as "subjected to"; "NS5-MTase" as "the NS5-MTase"; "by ADMET" as "by an ADMET"; "addition of" as "the addition of"; "removal of" as "the removal of"; "ranging 0.111" as "ranging from 0.111"; "zeaxanthin" as "and zeaxanthin". The grammar mistakes which are not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback regarding the grammatical and syntax errors in the manuscript. We have thoroughly reviewed the entire manuscript to identify and correct any other grammatical and syntax errors that were not mentioned. 2. There are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words "encode a" may be as "encodes a"; "decent" as "descent"; "Ligands" as "Ligand"; "best docked" as "best-docked"; "nor vaccines" as "no vaccines"; "other site" as "other side"; "rutin, has" as "rutin has"; "β-sitsterol" as "β-sitosterol or check correct spelling"; "caretenoids" as "carotenoids". The typos not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback 4in the manuscript. We have thoroughly reviewed the entire manuscript to manage necessary corrections. 3. Check the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the abstract (The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full) and the remaining part of the manuscript (For example, PDP, FDA, etc.,). Make a word abbreviated in the article that is repeated at least three times in the text, not all words to be abbreviated. Answer: Thank you for your suggestion. We have reviewed the manuscript to ensure that abbreviations are introduced upon first use and are only applied to terms repeated at least three times in the text, to maintain clarity and readability. 4. The full form of the species should be given when the first time appears in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Carica papaya when the first time appear and followed by C. papaya). Answer: Thank you for your suggestion. The corrections are made in the manuscript. 5. The authors should use uniformly either "ZIKA" or "Zika" all over the manuscript for better understanding. Answer: Thank you for your feedback. We have revised the manuscript to use "Zika" uniformly throughout the text for consistency and better understanding. 6. The authors may cite recent prevalence or incidence data Zika virus (ZIKV) infection and it should be at-least of 2022 or 2023. Answer : Thank you for your suggestion. We have updated the manuscript to include recent prevalence and incidence data on Zika virus infections from 2022 and 2023 to provide current and relevant information. 7. The introduction part appears less informative about Carica papaya, thus this section should be indicated as detailed to understand the manuscript in clear since the main objectives is focused on Carica papaya. The botanical description, family name and different plants of the plant with it medicinal uses. Answer: Thank you for your kind suggestion. We have updated the manuscript on the medicinal and botanical significance of papaya. 8. The authors should rewrite the following "The paper aims" as "The present work or study aims". Answer: Thank you for your suggestions. We have updated the manuscript. 9. The authors should avoid the repetition some content in the manuscript and also it affect the flow of reading. It should be carefully checked and removed. For example, the family name "Flaviviridae" of ZIKA has been mentioned in three times. Answer: Thank you for your feedback. We have carefully reviewed the manuscript and have reduced the redundant mentions of the family name "Flaviviridae" to improve clarity and coherence. 10. The conclusion seems in general. All conclusions must be convincing statements on what was found to be novel, impact based on the strong support of the review. Moreover, the authors may also be included the limitation of the present findings for a better understanding of the manuscript. Answer: Thank you for your valuable feedback. We have revised the conclusion to highlight the novel findings and their impact, ensuring that our statements are well-supported by the review. Additionally, we will include the limitations of the present study, such as the reliance on in silico methods, which need further validation through experimental and clinical studies. 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words "subjected for" may be as "subjected to"; "NS5-MTase" as "the NS5-MTase"; "by ADMET" as "by an ADMET"; "addition of" as "the addition of"; "removal of" as "the removal of"; "ranging 0.111" as "ranging from 0.111"; "zeaxanthin" as "and zeaxanthin". The grammar mistakes which are not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback regarding the grammatical and syntax errors in the manuscript. We have thoroughly reviewed the entire manuscript to identify and correct any other grammatical and syntax errors that were not mentioned. 2. There are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words "encode a" may be as "encodes a"; "decent" as "descent"; "Ligands" as "Ligand"; "best docked" as "best-docked"; "nor vaccines" as "no vaccines"; "other site" as "other side"; "rutin, has" as "rutin has"; "β-sitsterol" as "β-sitosterol or check correct spelling"; "caretenoids" as "carotenoids". The typos not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback 4in the manuscript. We have thoroughly reviewed the entire manuscript to manage necessary corrections. 3. Check the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the abstract (The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full) and the remaining part of the manuscript (For example, PDP, FDA, etc.,). Make a word abbreviated in the article that is repeated at least three times in the text, not all words to be abbreviated. Answer: Thank you for your suggestion. We have reviewed the manuscript to ensure that abbreviations are introduced upon first use and are only applied to terms repeated at least three times in the text, to maintain clarity and readability. 4. The full form of the species should be given when the first time appears in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Carica papaya when the first time appear and followed by C. papaya). Answer: Thank you for your suggestion. The corrections are made in the manuscript. 5. The authors should use uniformly either "ZIKA" or "Zika" all over the manuscript for better understanding. Answer: Thank you for your feedback. We have revised the manuscript to use "Zika" uniformly throughout the text for consistency and better understanding. 6. The authors may cite recent prevalence or incidence data Zika virus (ZIKV) infection and it should be at-least of 2022 or 2023. Answer : Thank you for your suggestion. We have updated the manuscript to include recent prevalence and incidence data on Zika virus infections from 2022 and 2023 to provide current and relevant information. 7. The introduction part appears less informative about Carica papaya, thus this section should be indicated as detailed to understand the manuscript in clear since the main objectives is focused on Carica papaya. The botanical description, family name and different plants of the plant with it medicinal uses. Answer: Thank you for your kind suggestion. We have updated the manuscript on the medicinal and botanical significance of papaya. 8. The authors should rewrite the following "The paper aims" as "The present work or study aims". Answer: Thank you for your suggestions. We have updated the manuscript. 9. The authors should avoid the repetition some content in the manuscript and also it affect the flow of reading. It should be carefully checked and removed. For example, the family name "Flaviviridae" of ZIKA has been mentioned in three times. Answer: Thank you for your feedback. We have carefully reviewed the manuscript and have reduced the redundant mentions of the family name "Flaviviridae" to improve clarity and coherence. 10. The conclusion seems in general. All conclusions must be convincing statements on what was found to be novel, impact based on the strong support of the review. Moreover, the authors may also be included the limitation of the present findings for a better understanding of the manuscript. Answer: Thank you for your valuable feedback. We have revised the conclusion to highlight the novel findings and their impact, ensuring that our statements are well-supported by the review. Additionally, we will include the limitations of the present study, such as the reliance on in silico methods, which need further validation through experimental and clinical studies. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 25 Jun 2024 kishore krishna kumaree , Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 25 Jun 2024 Author Response 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words "subjected for" may be as "subjected to"; "NS5-MTase" as "the ... Continue reading 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words "subjected for" may be as "subjected to"; "NS5-MTase" as "the NS5-MTase"; "by ADMET" as "by an ADMET"; "addition of" as "the addition of"; "removal of" as "the removal of"; "ranging 0.111" as "ranging from 0.111"; "zeaxanthin" as "and zeaxanthin". The grammar mistakes which are not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback regarding the grammatical and syntax errors in the manuscript. We have thoroughly reviewed the entire manuscript to identify and correct any other grammatical and syntax errors that were not mentioned. 2. There are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words "encode a" may be as "encodes a"; "decent" as "descent"; "Ligands" as "Ligand"; "best docked" as "best-docked"; "nor vaccines" as "no vaccines"; "other site" as "other side"; "rutin, has" as "rutin has"; "β-sitsterol" as "β-sitosterol or check correct spelling"; "caretenoids" as "carotenoids". The typos not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback 4in the manuscript. We have thoroughly reviewed the entire manuscript to manage necessary corrections. 3. Check the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the abstract (The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full) and the remaining part of the manuscript (For example, PDP, FDA, etc.,). Make a word abbreviated in the article that is repeated at least three times in the text, not all words to be abbreviated. Answer: Thank you for your suggestion. We have reviewed the manuscript to ensure that abbreviations are introduced upon first use and are only applied to terms repeated at least three times in the text, to maintain clarity and readability. 4. The full form of the species should be given when the first time appears in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Carica papaya when the first time appear and followed by C. papaya). Answer: Thank you for your suggestion. The corrections are made in the manuscript. 5. The authors should use uniformly either "ZIKA" or "Zika" all over the manuscript for better understanding. Answer: Thank you for your feedback. We have revised the manuscript to use "Zika" uniformly throughout the text for consistency and better understanding. 6. The authors may cite recent prevalence or incidence data Zika virus (ZIKV) infection and it should be at-least of 2022 or 2023. Answer : Thank you for your suggestion. We have updated the manuscript to include recent prevalence and incidence data on Zika virus infections from 2022 and 2023 to provide current and relevant information. 7. The introduction part appears less informative about Carica papaya, thus this section should be indicated as detailed to understand the manuscript in clear since the main objectives is focused on Carica papaya. The botanical description, family name and different plants of the plant with it medicinal uses. Answer: Thank you for your kind suggestion. We have updated the manuscript on the medicinal and botanical significance of papaya. 8. The authors should rewrite the following "The paper aims" as "The present work or study aims". Answer: Thank you for your suggestions. We have updated the manuscript. 9. The authors should avoid the repetition some content in the manuscript and also it affect the flow of reading. It should be carefully checked and removed. For example, the family name "Flaviviridae" of ZIKA has been mentioned in three times. Answer: Thank you for your feedback. We have carefully reviewed the manuscript and have reduced the redundant mentions of the family name "Flaviviridae" to improve clarity and coherence. 10. The conclusion seems in general. All conclusions must be convincing statements on what was found to be novel, impact based on the strong support of the review. Moreover, the authors may also be included the limitation of the present findings for a better understanding of the manuscript. Answer: Thank you for your valuable feedback. We have revised the conclusion to highlight the novel findings and their impact, ensuring that our statements are well-supported by the review. Additionally, we will include the limitations of the present study, such as the reliance on in silico methods, which need further validation through experimental and clinical studies. 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words "subjected for" may be as "subjected to"; "NS5-MTase" as "the NS5-MTase"; "by ADMET" as "by an ADMET"; "addition of" as "the addition of"; "removal of" as "the removal of"; "ranging 0.111" as "ranging from 0.111"; "zeaxanthin" as "and zeaxanthin". The grammar mistakes which are not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback regarding the grammatical and syntax errors in the manuscript. We have thoroughly reviewed the entire manuscript to identify and correct any other grammatical and syntax errors that were not mentioned. 2. There are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words "encode a" may be as "encodes a"; "decent" as "descent"; "Ligands" as "Ligand"; "best docked" as "best-docked"; "nor vaccines" as "no vaccines"; "other site" as "other side"; "rutin, has" as "rutin has"; "β-sitsterol" as "β-sitosterol or check correct spelling"; "caretenoids" as "carotenoids". The typos not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback 4in the manuscript. We have thoroughly reviewed the entire manuscript to manage necessary corrections. 3. Check the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the abstract (The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full) and the remaining part of the manuscript (For example, PDP, FDA, etc.,). Make a word abbreviated in the article that is repeated at least three times in the text, not all words to be abbreviated. Answer: Thank you for your suggestion. We have reviewed the manuscript to ensure that abbreviations are introduced upon first use and are only applied to terms repeated at least three times in the text, to maintain clarity and readability. 4. The full form of the species should be given when the first time appears in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Carica papaya when the first time appear and followed by C. papaya). Answer: Thank you for your suggestion. The corrections are made in the manuscript. 5. The authors should use uniformly either "ZIKA" or "Zika" all over the manuscript for better understanding. Answer: Thank you for your feedback. We have revised the manuscript to use "Zika" uniformly throughout the text for consistency and better understanding. 6. The authors may cite recent prevalence or incidence data Zika virus (ZIKV) infection and it should be at-least of 2022 or 2023. Answer : Thank you for your suggestion. We have updated the manuscript to include recent prevalence and incidence data on Zika virus infections from 2022 and 2023 to provide current and relevant information. 7. The introduction part appears less informative about Carica papaya, thus this section should be indicated as detailed to understand the manuscript in clear since the main objectives is focused on Carica papaya. The botanical description, family name and different plants of the plant with it medicinal uses. Answer: Thank you for your kind suggestion. We have updated the manuscript on the medicinal and botanical significance of papaya. 8. The authors should rewrite the following "The paper aims" as "The present work or study aims". Answer: Thank you for your suggestions. We have updated the manuscript. 9. The authors should avoid the repetition some content in the manuscript and also it affect the flow of reading. It should be carefully checked and removed. For example, the family name "Flaviviridae" of ZIKA has been mentioned in three times. Answer: Thank you for your feedback. We have carefully reviewed the manuscript and have reduced the redundant mentions of the family name "Flaviviridae" to improve clarity and coherence. 10. The conclusion seems in general. All conclusions must be convincing statements on what was found to be novel, impact based on the strong support of the review. Moreover, the authors may also be included the limitation of the present findings for a better understanding of the manuscript. Answer: Thank you for your valuable feedback. We have revised the conclusion to highlight the novel findings and their impact, ensuring that our statements are well-supported by the review. Additionally, we will include the limitations of the present study, such as the reliance on in silico methods, which need further validation through experimental and clinical studies. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 13 Jun 2023 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 2 (revision) 25 Jun 24 read read Version 1 13 Jun 23 read read read Arumugam Vijaya Anand , Bharathiar University, Coimbatore, India Luis Marquez-Dominguez , Instituto Mexicano del Seguro Social, Puebla, Mexico Tiratha Raj Singh , Jaypee University of Information Technology (JUIT), Himachal Pradesh, India Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Marquez-Dominguez L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Aug 2024 | for Version 2 Luis Marquez-Dominguez , Instituto Mexicano del Seguro Social, Puebla, Mexico 0 Views copyright © 2024 Marquez-Dominguez L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have made several corrections. However, in this revision, I have some comments or doubts that could better enrich the authors' work. Methods : The plant database is IMPPAT: Indian Medicinal Plants, Phytochemistry And Therapeutics, not IMPACT. Molecular Docking Results : Second Paragraph : The text "Figure 3A shows the heat map of the binding affinity of the ligands, with the lowest energy/highest affinity corresponding to red color, whereas the blue color indicates the highest binding energy or/lowest affinity." should be changed to "Figure 3A shows the heat map of the binding affinity of the ligands. The red color represents the lowest energy/highest affinity, while the blue color indicates the highest energy/lowest affinity." Page 5, Last Paragraph : The statement "rutin forms the highest number of hydrogen bonds involving 14 amino acid residues" is incorrect. Rutin interacts with 12 residues but generates two hydrogen bonds with two residues, Glu149 and His110. It is suggested to correct this. If the author wants to emphasize that there are two hydrogen bonds, they could indicate this by writing "2-E149," where the number corresponds to the hydrogen bonds formed with the residue. It is also recommended to list the amino acids in ascending order and use the one-letter nomenclature for the amino acids. Figure 3 : Order the red molecules at the top and the blue molecules at the bottom. This will allow a quick evaluation of which molecules are potential inhibitors. In the column titles, put the name or function of the enzyme and leave the PDB ID in parentheses. Figure 4 : The control should be the first to appear, as it is the reference for comparison. Reduce the number of structures presented. Select only two for each protein and two that inhibit both. For example, for 5WXB: Rutin and delta 7 avenasterol; for 5U04: delta 7 avenasterol and dehydrocarpaine. The other couplings can be included in the supplementary material. If possible, all structures should present the same pose to facilitate comparison of inhibitors for the same enzyme. Table 1 : Modify the amino acid nomenclature to one letter. Be careful with the number of amino acids. For example, pseudocarpaine lists Gly812, but 5WXB has only 195 amino acids. Remove the column title "Hydrophobic bond" and replace it with "Non-covalent interactions." Table 2 : Similar suggestions to Table 1. Mention in the text that the crystallized protein 5U04, according to the PDB sequence, has 598 amino acids, but parts of loops 1 (residues 340–363), 3 (residues 408–417), 4 (residues 454–471), 5 (residues 533–542), and 6 (residues 576–606) are missing in the model. This is in the reference for the crystallization of the model. Review the amino acid numbering; for example, gamma-carotene lists AL742, and cis-beta-carotene lists LA482 and RG483, alpha-carotene lists RP797, which are incorrect. Page 16 : The section "(BBB - permeability = YES or > 0.1); (GI - absorption = high); (Carcinogenicity = 0 to 0.3); (PAINS alert = 0) and (Lipinski’s violation = 0)" is disjointed from the text. Integrate it into the following paragraph, mentioning that these are the reference values for these variables. These would be my recommendations. Competing Interests No competing interests were disclosed. Reviewer Expertise virology, antiviral design, rational drug design, and enzyme kinetics, molecular biology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Marquez-Dominguez L. Peer Review Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.168075.r295619) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-655/v2#referee-response-295619 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Vijaya Anand A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 Jul 2024 | for Version 2 Arumugam Vijaya Anand , Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India 0 Views copyright © 2024 Vijaya Anand A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 1. This suggestion is not properly carried out and it should be rectified. The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full. Competing Interests No competing interests were disclosed. Reviewer Expertise Phytotherapeuics, Clinical Biochemistry, Medical Genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Vijaya Anand A. Peer Review Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.168075.r295618) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-655/v2#referee-response-295618 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Singh T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 Sep 2024 | for Version 1 Tiratha Raj Singh , Jaypee University of Information Technology (JUIT), Himachal Pradesh, India 0 Views copyright © 2024 Singh T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The article titled " In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein" by Kumaree et al is an interesting piece of work where authors have utilized in details all the structural bioinformatics components to analyze and annotate data utilized for the design of novel inhibitors for Zika virus protein. They also proposed that their studies results will be confirmed if experimental validations could be done in future. There are some typos and minor grammar issues along with the abbreviations used in the manuscript. Authors are suggested to rectify all these issues. There is no separate conclusion added, it should be added with specific outcomes of the study. Use of either “ZIKA” or “Zika” all over the manuscript be a better idea for making it uniform? Are there any other phytocompounds in the mentioned plant, which could be used for further studies.As the used compounds are naturally available, are their IC50 values available. If yes authors may compile this information for the readers, will add value to the research. There are some good articles such as: [ ref 1 ], which can also help the authors to look for technical contents for the refinements of the overall process. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Shukla R, Chandra A, Kumar A, Kandpal P, et al.: Repurposing of drugs against methyltransferase as potential Zika virus therapies. Sci Rep . 2023; 13 (1): 7870 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Bioinformatics and Systems Biology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Singh TR. Peer Review Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r273118) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-273118 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Marquez-Dominguez L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 29 May 2024 | for Version 1 Luis Marquez-Dominguez , Instituto Mexicano del Seguro Social, Puebla, Mexico 0 Views copyright © 2024 Marquez-Dominguez L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The quest for compounds exhibiting antiviral activity against diseases such as Zika is of paramount importance, given the absence of a definitive treatment for this ailment. However, I have several suggestions and reservations regarding the manuscript's content. Among the significant revisions required, it is observed that one of the receptors does not correspond to the Zika virus. Until the authors clarify this discrepancy, the integrity of the results, discussion, conclusions remains questionable. 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus diagram, rather than just a segment of it. 2. Concerning the selection of receptors, the NS5 RdRp with PDB key 5UO4 corresponds to the Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)ethyl) benzonitrile, and not to the NS5 RdRp of the Zika virus. This discrepancy is also evident in the supplementary data. Was all docking and figure rendering performed using the 5UO4 structure, which does not represent the Zika NS5 RdRp? If so, a substantial portion of the results may not be reflective. I recommend a thorough verification. When compared with NS5 RdRp structures with PDB codes 5Wz3 or 5U0B, there appears to be no similarity. 3. The methodology mentions obtaining 9 coupling results, yet it fails to specify the criteria used to select the optimal molecular coupling model. Please provide clarity on the selection process. 4. In the section on "Ligand and receptor molecular docking," the size of the grid is redundantly stated. 5. In the "Result Molecular Docking" section, the references for the positive ligands (controls) do not support their selection. For example, concerning sinefungin, it is mentioned that they were designed by HVC, but there is no information related to flavivirus or Zika. The same applies to sofosbuvir. I suggest modifying the references to accurately reflect their relevance. 6. The images exhibit low resolution, hindering effective structure visualization. Therefore, I recommend enhancing clarity for better interpretation. Specifically, in Figure 4, the sharpness is insufficient for clear visualization of 2D diagrams, and the residues interacting with molecules are not distinguishable from the representation of alpha helices and beta sheets. The legend of interactions is unreadable, and the figure caption lacks information on the meaning of each color. For improved comparison, I suggest including controls (sofosbuvir and sinefungin) in Figure 4. Additionally, consider incorporating a surface representation with electrostatic charges to highlight hydrophobic regions or regions with electrostatic charges interacting with molecules. 7. In Figure 3, in the 5UO4 table, the control -7.40 should be white as it serves as the reference. It appears blue, possibly due to incorrectly taking the positive ligand of 5WXB as a reference. This is inaccurate, as it is a receptor and a distinct molecule. 8. Table 1 in the docking results mentions different types of non-covalent interactions without justifying why only hydrogen bond bonds and hydrophobic interactions were considered. The discussion also lacks insights into the differences or importance of various interactions such as alkyl-alkyl, pi-alkyl, etc. I recommend ordering the amino acids in ascending order for clarity. 9. In the discussion of interactions between molecules (rutin) versus sofosbuvir, there is mention of a greater number of interactions, but the explanation on how these interactions lead to blocking the active site is lacking. Consider discussing whether this blocking results from size or other characteristics inherent to enzymatic activity inhibition. A more in-depth discussion of the results is suggested. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Not applicable Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly References 1. Noreen, Ali R, Badshah SL, Faheem M, et al.: Identification of potential inhibitors of Zika virus NS5 RNA-dependent RNA polymerase through virtual screening and molecular dynamic simulations. Saudi Pharm J . 2020; 28 (12): 1580-1591 PubMed Abstract | Publisher Full Text 2. Lim SP, Noble CG, Shi PY: The dengue virus NS5 protein as a target for drug discovery. Antiviral Res . 2015; 119 : 57-67 PubMed Abstract | Publisher Full Text 3. Song W, Zhang H, Zhang Y, Chen Y, et al.: Identification and Characterization of Zika Virus NS5 Methyltransferase Inhibitors. Front Cell Infect Microbiol . 2021; 11 : 665379 PubMed Abstract | Publisher Full Text 4. Ramharack P, Soliman MES: Zika virus NS5 protein potential inhibitors: an enhanced in silico approach in drug discovery. J Biomol Struct Dyn . 2018; 36 (5): 1118-1133 PubMed Abstract | Publisher Full Text 5. Nascimento IJDS, Santos-Júnior PFDS, Aquino TM, Araújo-Júnior JX, et al.: Insights on Dengue and Zika NS5 RNA-dependent RNA polymerase (RdRp) inhibitors. Eur J Med Chem . 2021; 224 : 113698 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise virology, antiviral design, rational drug design, and enzyme kinetics, molecular biology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 25 Jun 2024 kishore krishna kumaree, Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 1. In Figure 1, the depiction of structural and non-structural proteins aligns with the complete genome. Therefore, I recommend that the box should encompass the entire genome in the virus diagram, rather than just a segment of it. Answer: Thank you for your suggestion, We have replaced the figure 1 with a new figure in the manuscript. 2. Concerning the selection of receptors, the NS5 RdRp with PDB key 5UO4 corresponds to the Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)ethyl) benzonitrile, and not to the NS5 RdRp of the Zika virus. This discrepancy is also evident in the supplementary data. Was all docking and figure rendering performed using the 5UO4 structure, which does not represent the Zika NS5 RdRp? If so, a substantial portion of the results may not be reflective. I recommend a thorough verification. When compared with NS5 RdRp structures with PDB codes 5Wz3 or 5U0B, there appears to be no similarity. Answer: Thank you for your meticulous review and valuable feedback. I sincerely apologize for the oversight regarding the receptor used in our study. There was indeed a typographical error in the manuscript. The correct PDB code for the Zika virus NS5 RdRp that we used for our analyses is 5U04, not 5UO4. I assure you that all docking and technical analyses were conducted using the 5U04 structure, which accurately represents the Zika NS5 RdRp. The incorrect PDB code in the text was an unfortunate typographical mistake, and we will promptly correct this in the manuscript and the supplementary data to reflect the accurate PDB code. We greatly appreciate your diligence in pointing out this discrepancy and apologize for any confusion it may have caused. Your feedback is crucial for maintaining the integrity of our work, and we will ensure that such errors are rectified to convey our research findings accurately. 3. The methodology mentions obtaining 9 coupling results, yet it fails to specify the criteria used to select the optimal molecular coupling model. Please provide clarity on the selection process. Answer: The selection of the optimal molecular model was done based on the lower binding energy (more negative value), a higher number of hydrogen bonds, and other nonbonded interactions, including hydrophobic and electrostatic interactions. In addition, conserved binding pocket interactions were also considered and compared with the known control inhibitors for the respective target proteins.We believe this multifaceted approach provides a more robust optimal model selection. 4. In the section on "Ligand and receptor molecular docking," the size of the grid is redundantly stated. Answer: The redundancy mentioning of grid size has been corrected in the revised manuscript. 5. In the "Result Molecular Docking" section, the references for the positive ligands (controls) do not support their selection. For example, concerning sinefungin, it is mentioned that they were designed by HVC, but there is no information related to flavivirus or Zika. The same applies to sofosbuvir. I suggest modifying the references to accurately reflect their relevance. Answer: Thank you for your careful review and for highlighting the need to ensure the references for our positive control ligands are accurate and relevant. We apologize for any oversight in the current references and appreciate your suggestion to provide more relevant citations. In response to your concern and to support our selection, we have updated the manuscript and have included the following references: Sinefungin and Sofosbuvir were the reference inhibitors for NS5-MTase and NS5 RdRp, respectively. References: Hercik, K., et al., Structural basis of Zika virus methyltransferase inhibition by sinefungin. Archives of virology, 2017. 162 : p. 2091-2096. Lin, Y., et al., Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors. International journal of antimicrobial agents, 2019. 54 (4): p. 502-506. Sacramento, C.Q., et al., The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Scientific reports, 2017. 7 (1): p. 40920. Tao, Z., et al., Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives. European Journal of Medicinal Chemistry, 2018. 157 : p. 994-1004. 6. The images exhibit low resolution, hindering effective structure visualization. Therefore, I recommend enhancing clarity for better interpretation. Specifically, in Figure 4, the sharpness is insufficient for clear visualization of 2D diagrams, and the residues interacting with molecules are not distinguishable from the representation of alpha helices and beta sheets. The legend of interactions is unreadable, and the figure caption lacks information on the meaning of each color. For improved comparison, I suggest including controls (sofosbuvir and sinefungin) in Figure 4. Additionally, consider incorporating a surface representation with electrostatic charges to highlight hydrophobic regions or regions with electrostatic charges interacting with molecules. Answer: Thank you for your constructive feedback regarding the visualization quality of the images in Figure 4. We have considered your recommendations and replaced the images with higher-resolution versions to enhance clarity and facilitate better interpretation. However, at this stage, we have not incorporated surface representations with electrostatic charges to highlight hydrophobic regions and regions with electrostatic interactions. We will consider including these enhancements in future revisions to improve the visualization quality further. Additionally, we have included controls (sofosbuvir and sinefungin) in Figure 4 for improved comparison. We appreciate your valuable feedback, which has significantly improved the quality and clarity of our manuscript. Thank you for your continued support in refining our research. 7. In Figure 3, in the 5UO4 table, the control -7.40 should be white as it serves as the reference. It appears blue, possibly due to incorrectly taking the positive ligand of 5WXB as a reference. This is inaccurate, as it is a receptor and a distinct molecule. Answer: Thank you for pointing out the issue with the color assignment in Figure 3. We have redone the color mapping for the complexes 5U04 and 5WXB table in Figure 3. The new figure has been added to the manuscript. 8. Table 1 in the docking results mentions different types of non-covalent interactions without justifying why only hydrogen bond bonds and hydrophobic interactions were considered. The discussion also lacks insights into the differences or importance of various interactions such as alkyl-alkyl, pi-alkyl, etc. I recommend ordering the amino acids in ascending order for clarity. Answer: Thank you for your insightful feedback regarding the non-covalent interactions mentioned in Table 1 of the docking results. In our study, we focused on hydrogen bonds and hydrophobic interactions due to their significant roles in stabilizing ligand binding within the receptor's active site. Hydrogen bonds are essential for providing specificity and strong directional interactions, while hydrophobic interactions contribute to binding affinity by facilitating the burial of non-polar surfaces and reducing desolvation penalties. Although other non-covalent interactions such as alkyl-alkyl, pi-alkyl, and pi-pi interactions also play important roles in ligand-receptor binding, we prioritized hydrogen bonds and hydrophobic interactions due to their dominant influence in many docking studies. We have also included an explanation in the manuscript's discussion section. Furthermore, we have arranged the amino acids in Table 1 in their chronological order of occurrence within the protein sequence and structure, reflecting the sequential interaction pattern and spatial context, which is crucial for understanding the binding interactions. This arrangement aids in visualizing the interactions as they occur along the protein's active site and aligns with standard conventions in protein interaction studies. 9. In the discussion of interactions between molecules (rutin) versus sofosbuvir, there is mention of a greater number of interactions, but the explanation on how these interactions lead to blocking the active site is lacking. Consider discussing whether this blocking results from size or other characteristics inherent to enzymatic activity inhibition. A more in-depth discussion of the results is suggested. Answer: Thank you for your valuable feedback and suggestion for a more in-depth discussion of the interactions between rutin and sofosbuvir To address the interactions between rutin and sofosbuvir with the active site, we provide a more detailed discussion on how these interactions contribute to the inhibition of enzymatic activity. Rutin exhibits a greater number of interactions compared to sofosbuvir, which enhances its ability to effectively block the active site. This blocking is not solely a function of the number of interactions but also their nature and strength. The larger size of rutin allows it to span a broader area of the active site, facilitating multiple points of contact through hydrogen bonds, hydrophobic interactions, and aromatic stacking. These interactions collectively stabilize the binding of rutin within the active site, thereby preventing substrate access and subsequent enzymatic activity. In contrast, while sofosbuvir also forms stable interactions, the fewer number and potentially weaker nature of these interactions may result in less effective blocking. Thus, rutin's increased binding affinity and comprehensive interaction profile contribute to its potential as a more effective inhibitor of the enzyme's active site. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Marquez-Dominguez L. Peer Review Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r228783) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-655/v1#referee-response-228783 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Vijaya Anand A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 Oct 2023 | for Version 1 Arumugam Vijaya Anand , Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India 0 Views copyright © 2023 Vijaya Anand A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have put effort to evaluate the “ In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5”. The authors describe the research undertaken with this in an organized manner, emphasizing the results obtained by them. The article needs modification for better cohesion of information to achieve the goal and the shortcomings which need to be considered. Hence, the paper can be approved after MAJOR REVISIONS are carried out. 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words “subjected for” may be as “subjected to”; “NS5-MTase” as “the NS5-MTase”; “by ADMET” as “by an ADMET”; “addition of” as “the addition of”; “removal of” as “the removal of”; “ranging 0.111” as “ranging from 0.111”; “zeaxanthin” as “and zeaxanthin”. The grammar mistakes which are not mentioned here are also to be checked and corrected properly. 2. There are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words “encode a” may be as “encodes a”; “decent” as “descent”; “Ligands” as “Ligand”; “best docked” as “best-docked”; “nor vaccines” as “no vaccines”; “other site” as “other side”; “rutin, has” as “rutin has”; “β-sitsterol” as “β-sitosterol or check correct spelling”; “caretenoids” as “carotenoids”. The typos not mentioned here are also to be checked and corrected properly. 3. Check the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the abstract (The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full) and the remaining part of the manuscript (For example, PDP, FDA, etc.,). Make a word abbreviated in the article that is repeated at least three times in the text, not all words to be abbreviated. 4. The full form of the species should be given when the first time appears in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Carica papaya when the first time appear and followed by C. papaya ). 5. The authors should use uniformly either “ZIKA” or “Zika” all over the manuscript for better understanding. 6. The authors may cite recent prevalence or incidence data Zika virus (ZIKV) infection and it should be at-least of 2022 or 2023. 7. The introduction part appears less informative about Carica papaya , thus this section should be indicated as detailed to understand the manuscript in clear since the main objectives is focused on Carica papaya . The botanical description, family name and different plants of the plant with it medicinal uses. 8. The authors should rewrite the following “The paper aims” as “The present work or study aims”. 9. The authors should avoid the repetition some content in the manuscript and also it affect the flow of reading. It should be carefully checked and removed. For example, the family name “Flaviviridae” of ZIKA has been mentioned in three times. 10. The conclusion seems in general. All conclusions must be convincing statements on what was found to be novel, impact based on the strong support of the review. Moreover, the authors may also be included the limitation of the present findings for a better understanding of the manuscript. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Not applicable Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Phytotherapeuics, Clinical Biochemistry, Medical Genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 25 Jun 2024 kishore krishna kumaree, Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand 1. The English need improvement since there are some grammatical and syntax errors in the manuscript. For example, the words "subjected for" may be as "subjected to"; "NS5-MTase" as "the NS5-MTase"; "by ADMET" as "by an ADMET"; "addition of" as "the addition of"; "removal of" as "the removal of"; "ranging 0.111" as "ranging from 0.111"; "zeaxanthin" as "and zeaxanthin". The grammar mistakes which are not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback regarding the grammatical and syntax errors in the manuscript. We have thoroughly reviewed the entire manuscript to identify and correct any other grammatical and syntax errors that were not mentioned. 2. There are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words "encode a" may be as "encodes a"; "decent" as "descent"; "Ligands" as "Ligand"; "best docked" as "best-docked"; "nor vaccines" as "no vaccines"; "other site" as "other side"; "rutin, has" as "rutin has"; "β-sitsterol" as "β-sitosterol or check correct spelling"; "caretenoids" as "carotenoids". The typos not mentioned here are also to be checked and corrected properly. Answer: Thank you for your detailed feedback 4in the manuscript. We have thoroughly reviewed the entire manuscript to manage necessary corrections. 3. Check the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the abstract (The use of abbreviations in the abstract (ADME) section may distract readers who wish to quickly skim through several publications before deciding to read one in full) and the remaining part of the manuscript (For example, PDP, FDA, etc.,). Make a word abbreviated in the article that is repeated at least three times in the text, not all words to be abbreviated. Answer: Thank you for your suggestion. We have reviewed the manuscript to ensure that abbreviations are introduced upon first use and are only applied to terms repeated at least three times in the text, to maintain clarity and readability. 4. The full form of the species should be given when the first time appears in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Carica papaya when the first time appear and followed by C. papaya). Answer: Thank you for your suggestion. The corrections are made in the manuscript. 5. The authors should use uniformly either "ZIKA" or "Zika" all over the manuscript for better understanding. Answer: Thank you for your feedback. We have revised the manuscript to use "Zika" uniformly throughout the text for consistency and better understanding. 6. The authors may cite recent prevalence or incidence data Zika virus (ZIKV) infection and it should be at-least of 2022 or 2023. Answer : Thank you for your suggestion. We have updated the manuscript to include recent prevalence and incidence data on Zika virus infections from 2022 and 2023 to provide current and relevant information. 7. The introduction part appears less informative about Carica papaya, thus this section should be indicated as detailed to understand the manuscript in clear since the main objectives is focused on Carica papaya. The botanical description, family name and different plants of the plant with it medicinal uses. Answer: Thank you for your kind suggestion. We have updated the manuscript on the medicinal and botanical significance of papaya. 8. The authors should rewrite the following "The paper aims" as "The present work or study aims". Answer: Thank you for your suggestions. We have updated the manuscript. 9. The authors should avoid the repetition some content in the manuscript and also it affect the flow of reading. It should be carefully checked and removed. For example, the family name "Flaviviridae" of ZIKA has been mentioned in three times. Answer: Thank you for your feedback. We have carefully reviewed the manuscript and have reduced the redundant mentions of the family name "Flaviviridae" to improve clarity and coherence. 10. The conclusion seems in general. All conclusions must be convincing statements on what was found to be novel, impact based on the strong support of the review. Moreover, the authors may also be included the limitation of the present findings for a better understanding of the manuscript. Answer: Thank you for your valuable feedback. We have revised the conclusion to highlight the novel findings and their impact, ensuring that our statements are well-supported by the review. Additionally, we will include the limitations of the present study, such as the reliance on in silico methods, which need further validation through experimental and clinical studies. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Vijaya Anand A. Peer Review Report For: In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein [version 2; peer review: 3 approved] . F1000Research 2024, 12 :655 ( https://doi.org/10.5256/f1000research.148054.r214337) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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