Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches

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Most people with COVID-19 experience mild to moderate symptoms and recover without the need for special treatments. The SARS‑CoV‑2 RNA‑dependent RNA polymerase (RdRp) plays a crucial role in the viral life cycle. The active site of the RdRp is a very accessible region, so targeting this region to study the inhibition of viral replication may be an effective therapeutic approach. For this reason, this study has selected and analysed a series of ligands used as SARS-CoV-2 virus inhibitors, namely: Darunavir (Daru), Dexamethasona (Dexame), Dolutegravir (Dolu), Fosamprenavir (Fosam), Ganciclovir (Gan), Insoine (Inso), Lopinavir (Lop), Ritonavir (Rito) and Tipranavir (Tipra). Methods These ligands were analyzed using molecular docking, molecular quantum similarity using four similarity indices like overlap, Coulomb and their Euclidean distances. On the other hand, these outcomes were supported with chemical reactivity indices defined within a conceptual density functional theory framework. Results The results show the conformations with the highest root-mean-square deviation (RMSD), have π-π stacking interaction with residue LYS621, ARG555 and ASP623, CYS622, ASP760, among others. In the molecular quantum similarity, the highest indices have been obtained in the electronic similarity in comparison with the structural similarity. Conclusions These studies allow the identification of the main stabilizing interactions using the crystal structure of SARS‑CoV‑2 RNA‑dependent RNA polymerase. In this order of ideas, this study provides new insights into these ligands that can be used in the design of new COVID-19 treatments. The studies allowed us to find an explanation supported in the Density Functional Theory about the chemical reactivity and the stabilization in the active site of the ligands. " } { "@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/12-669", "name": "Understanding the high electronic quantum similarity of a series of..." } } ] } Home Browse Understanding the high electronic quantum similarity of a series of... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Morales-Bayuelo A and Sánchez-Márquez J. Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.12688/f1000research.127061.2 ) 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 Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] Alejandro Morales-Bayuelo https://orcid.org/0000-0001-9159-5289 1 , Jesús Sánchez-Márquez 2 Alejandro Morales-Bayuelo https://orcid.org/0000-0001-9159-5289 1 , Jesús Sánchez-Márquez 2 PUBLISHED 06 Feb 2024 Author details Author details 1 Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia 2 Department of Chemistry-Physics, Science Faculty, Río San Pedro University Campus, Cádiz University, Cádiz, Spain Alejandro Morales-Bayuelo Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Jesús Sánchez-Márquez Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Emerging Diseases and Outbreaks gateway. This article is included in the Bioinformatics gateway. This article is included in the Cell & Molecular Biology gateway. This article is included in the Cheminformatics gateway. This article is included in the Virus Bioinformatics collection. Abstract Background A coronavirus identified in 2019, SARS-CoV-2, has caused a pandemic of respiratory illness, called COVID-19. Most people with COVID-19 experience mild to moderate symptoms and recover without the need for special treatments. The SARS‑CoV‑2 RNA‑dependent RNA polymerase (RdRp) plays a crucial role in the viral life cycle. The active site of the RdRp is a very accessible region, so targeting this region to study the inhibition of viral replication may be an effective therapeutic approach. For this reason, this study has selected and analysed a series of ligands used as SARS-CoV-2 virus inhibitors, namely: Darunavir (Daru), Dexamethasona (Dexame), Dolutegravir (Dolu), Fosamprenavir (Fosam), Ganciclovir (Gan), Insoine (Inso), Lopinavir (Lop), Ritonavir (Rito) and Tipranavir (Tipra). Methods These ligands were analyzed using molecular docking, molecular quantum similarity using four similarity indices like overlap, Coulomb and their Euclidean distances. On the other hand, these outcomes were supported with chemical reactivity indices defined within a conceptual density functional theory framework. Results The results show the conformations with the highest root-mean-square deviation (RMSD), have π-π stacking interaction with residue LYS621, ARG555 and ASP623, CYS622, ASP760, among others. In the molecular quantum similarity, the highest indices have been obtained in the electronic similarity in comparison with the structural similarity. Conclusions These studies allow the identification of the main stabilizing interactions using the crystal structure of SARS‑CoV‑2 RNA‑dependent RNA polymerase. In this order of ideas, this study provides new insights into these ligands that can be used in the design of new COVID-19 treatments. The studies allowed us to find an explanation supported in the Density Functional Theory about the chemical reactivity and the stabilization in the active site of the ligands. READ ALL READ LESS Keywords RNA dependent RNA polymerase SARS-CoV-2 virus, COVID-19 treatments, molecular docking, molecular quantum similarity, chemical reactivity descriptors, density functional theory. Corresponding Author(s) Alejandro Morales-Bayuelo ( [email protected] ) Close Corresponding author: Alejandro Morales-Bayuelo Competing interests: No competing interests were disclosed. Grant information: This work was supported by Fundación Universitaria Tecnológico Comfenalco, grant number CIPTEC-2022-I, awarded to Alejandro Morales-Bayuelo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Morales-Bayuelo A and Sánchez-Márquez J. 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: Morales-Bayuelo A and Sánchez-Márquez J. Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.12688/f1000research.127061.2 ) First published: 14 Jun 2023, 12 :669 ( https://doi.org/10.12688/f1000research.127061.1 ) Latest published: 06 Feb 2024, 12 :669 ( https://doi.org/10.12688/f1000research.127061.2 ) Revised Amendments from Version 1 The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn't exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. The human body maintains various pH levels in different parts, and this plays a role in the virus's ability to infect cells. Also in the methodology related with molecular docking was place this line “All molecular Docking has been supported by a molecular dynamic of 30ns.” The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn't exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. The human body maintains various pH levels in different parts, and this plays a role in the virus's ability to infect cells. Also in the methodology related with molecular docking was place this line “All molecular Docking has been supported by a molecular dynamic of 30ns.” See the authors' detailed response to the review by Kiran Bharat Lokhande READ REVIEWER RESPONSES Introduction Coronaviruses are the family of viruses to which SARS-CoV-2 belongs, the virus causing the COVID-19 pandemic. They were discovered in the 1960s, but their origin is still unknown. 1 Their different types cause different illnesses, from a cold to severe respiratory illness (a severe form of pneumonia). Most coronaviruses are not dangerous and can be treated effectively. In fact, most people contract a coronavirus at some point in their lives, usually during their childhood. 1 Although they are more frequent in autumn or winter, they can be found at any time of the year. 1 – 3 The coronavirus owes its name to the appearance it presents, since it is very similar to a crown or a halo. It is a type of virus present mainly in animals, but also in humans. In recent years, 4 three major epidemic outbreaks caused by new coronaviruses have been described. COVID-19/SARS-CoV-2: at the end of December 2019, 4 , 5 the first cases of a new coronavirus were reported in the city of Wuhan (China). Since then, the increase in new infections with the SARS-CoV-2 virus (initially called 2019nCoV), which causes the disease called COVID-19, has been continuous and its transmission from person to person has accelerated. 5 Reported cases already far exceed those of the 2002-2003 SARS epidemic. 4 , 5 SARS’s fatality rate is lower than that of other coronaviruses, but many more deaths are occurring (there are already more than 5 million, because the infected people number in the hundreds of millions worldwide (almost 300 million in early January 2022). 4 – 6 There is no specific treatment for SARS-CoV-2, but multiple drugs, alone or in combination, are being investigated, as well as the use of plasma from patients who have recovered. 6 – 8 The usefulness of the other drugs, which are being administered to patients in clinical trials or for compassionate use, are being studied. For example, Remdesivir is an antiviral drug that was initially developed for the disease caused by the Ebola virus but has also shown in vitro activity against SARS-CoV-2. 9 However, the results of this treatment have not been as satisfactory as expected. 9 , 10 Ritonavir/lopinavir is a combination that is usually used against HIV. 10 Lopinavir inhibits some enzymes involved in the virus multiplication cycle, while ritonavir acts as a protector of lopinavir because it degrades very quickly. 10 The use of hydroxychloroquine against the new coronavirus has been very controversial. The Spanish Agency for Medicines and Health Products (Aemps) warns that this medicine “has been shown to be effective against SARS-CoV-2 in in vitro studies, but there is still no solid scientific evidence on its efficacy against Covid-19 in humans”. 11 Finally, Dexamethasone is a corticosteroid that is emerging as an option for the most serious cases of COVID-19, since it could reduce mortality. 12 These compounds are combined with other anti-inflammatory or virus-inhibiting substances, as well as with antibiotics (to treat or prevent secondary bacterial infections) and cytokine inhibitors. 13 As for the treatment for infections caused by cold coronaviruses, cases are usually mild and are overcome by following the same steps as with a common cold, 13 , 14 a new alternative to the treatment for the COVID-19 is needed to improve therapeutic alternatives for this disease that has claimed the lives of multiple people around the world. A series of compounds used, tested, and associated as treatments for SARS-CoV-2 have been selected for this study. These compounds are: Darunavir (Daru), Dexamethasona (Dexame), Dolutegravir (Dolu), Fosamprenavir (Fosam), Ganciclovir (Gan), Insoine (Inso), Lopinavir (Lop), Ritonavir (Rito) and Tipranavir (Tipra). They are related to molecular treatment against SARS-CoV-2 in vitro studies, have been analysed in this study using theoretical techniques such as molecular docking, molecular quantum similarity (MQS) and chemical reactivity descriptors within the Density Functional Theory (DFT). In our previous publication, 15 ligands Ascorbic acid Vitamin C (Asco), Azithromycin (Azythr), Cholecalciferol Vitamin D (Chole) and Hydroxychoroquine (Hidrox); other less known ones such as Abacavir, Acyclovir (Acyc), Amprenavir (Ampre), Baloxavir (Balox), Boceprevir (Boce), Cidofovir (Cido), Edoxudine (Edox) and Emtricitabine (Emitri) were used considering their association for the treatment of SARS-CoV-2. However, in the present study (the second part of an overarching study), a set of entirely different ligands, taking into account the molecular diversity from structural and electronic point of view, have been used to extrapolate and obtain new insights for the SARS-CoV-2 treatment today. The difference between the previous set of ligands 15 and the set reported here, is the molecular quantum similarity. The set studied in this work has greater electronic quantum similarity than those presented in Ref. 15 , and thus warrants a separate study to specifically investigate the associated impacts of quantum similarity on the results. Methods System preparation To conduct the docking analysis, the receptor structures discussed in open access References 9 – 14 for the docking experiment were extricated utilizing the following protocols through the crystal Structure of SARS-CoV-2 RNA-dependent RNA polymerase, using Protein Data Bank ( 6M71 ), see also Underlying data , which was adjusted utilizing the protein preparation wizard module of the openly available input file for Schrödinger suite 2017-1. The system preparation has been implemented followed these steps: i) A key factor on the docking results is the hydrogen bond. For these reasons the hydrogen bond (H-bond) network was optimized, and the protein structure was refined, at physiological pH. This weight was optimized based on the premise that high-resolution structures accurately reflect hydrogen bonding in proteins. ii) The charge of the ligands on the active site is crucial on the stabilization in the active site. Taking this into account, the protonation states were determined using PropKa utility, part of the Schrödinger suite. This program reaffirms the ionic character of compounds and predicts the pKa values of ionizable groups in proteins and protein-ligand complexes based in the 3D structure. iii) The possible correlation effects in the heavy atoms were corrected using the Impact Refinement (Impref) module to execute a restrained molecular minimization with heavy atoms constrained to a low root-mean-square deviation (RMSD) from the initial coordinates. 16 – 18 It is helpful to arrange the observations in serial order of the independent variable when one of the two variables is clearly identifiable as independent. The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it’s important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn’t exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. Molecular docking In our research group the calculation (docking results) were carried out through the freely available Schrödinger suite using the Glide, 19 , 20 Glide is the program of the Schrödinger suite and was used to obtain the docking results. This program was used with default parameters (that is, the number of poses written per ligand was set to 10,000, and the scaling factors of the vdW radii and the partial atomic charge cut-off were set to the default values 0.80 and 0.15, respectively) and Standard Precision (SP) model has been used for docking outcomes. One of the most important parameters about the docking analysis is the grid. The grid generation implementation has been benchmarked using the target protein of SARS-CoV-2 RNA-dependent RNA polymerase. All molecular Docking has been supported by a molecular dynamic of 30 ns. Quantum similarity analysis Molecular quantum similarity measure An important feature associated with structural and electronic point of view is the Molecular Quantum Similarity Measure (MQSM). The MQSM of the systems A and B, known as Z AB , is obtained using the Density Functions (DFs) using Eq. (1) . (1) Z AB = ρ A Ω ρ B = ∬ ρ A r 1 Ω r 1 r 2 ρ B r 2 dr 1 dr 2 Studying the nature of the operator Ω( r 1 , r 2 ) with electronic densities for A and B, 21 – 26 used in Equation 1 , provides the information being compared between the two systems while simultaneously designating our measure of similarity. For instance, if the chosen operator is the Dirac delta function (an efficient approach for functions with high peak values, such as the electronic density), i.e., Ω( r 1 , r 2 ) = δ( r 1 - r 2 ). 26 – 33 Another widely used alternative is the Coulomb operator, i.e., Ω( r 1 , r 2 ) = | r ‌ 1 - r 2 |‌‌ -1 , resulting in a Coulombic MQSM. 34 – 36 Chemical reactivity outcomes Previously, several investigations have shown the relationship between quantum similarity and chemical reactivity descriptors. 37 – 47 In addition, the quantum similarity and DFT uses the density function as an object of study of the similarity indexes; specifically, the Coulomb index can be related to electronic factors associated with chemical reactivity. Using the Frontier Molecular Orbitals (FMO) and the energy gap, the global reactivity indices, such as chemical potential ( μ ), 48 hardness ( ɳ ), 49 and electrophilicity ( ω ), 48 , 49 will be calculated. These chemical reactivity indices ( Eqs. 2 - 4 ) give an idea about the stability of the systems. The chemical potential measures the inclination of electrons to leave the equilibrium system, 48 whereas chemical hardness measures the resistance of a chemical species to change its electronic configuration. 39 (2) μ ≈ E LUMO + E HOMO 2 (3) η ≈ E LUMO − E HOMO Electrophilicity index ( ω ) measure the stabilization energy of the system when it is saturated by electrons from the external environment and is mathematically defined as 48 , 49 : (4) ω = μ 2 2 η In this work, the local reactivity descriptors are the Fukui functions. Equations (5 , 6) represents the response of the chemical potential of a system to changes in the external potential. (5) f + ( r → ) ≈ LUMO ( r → ) 2 (6) f − ( r → ) ≈ HOMO ( r → ) 2 Where ( f + ( r → ) ) is for nucleophilic attack and ( f − ( r → ) ) for the electrophilic attack. 50 – 54 All the calculations were carried out using the method B3LYP. B3LYP is one of the most used Density-Functional Theory (DFT) approaches. It is capable of predicting molecular structures and other properties according to the experimental data 55 and the basis set 6-311G (d,p) 56 which is the result of adding a correction to the 6-311G(d) basis set leading to calculations of electronegativity, hardness, reactivity indices and frontier molecular orbitals with a similar quality to those obtained with much larger basis sets (such as Aug-cc-pVQZ and Aug-cc-pV5Z). This method/basis set has been used in combination with Gaussian 16 package 57 and GaussView, Version 6.1 58 a free, alternative software that carries out a similar function is ORCA 5.0.3. Results and discussion Molecular analysis One of the objectives of this project involves an analysis about molecular coupling of the compounds on the active site. For this reason, a study about the best conformations on the active site of the selected compounds was carried out. Please note that all files associated with the results are available in Underlying data. 59 Figure 1 shows the conformation with the highest RMSD, in this conformation Lopinavir has a π-π stacking interaction with residue LYS621 with a length of 1.56Å. On the other hand, with this same residue they have an H-bond with a length of 1.62Å and 1.72Å, respectively. Additionally, this compound has an H-bond with residues ARG553, ARG555 and ASP623 with lengths of 1.56Å, 1.64Å and 1.42Å, respectively. Figure 1. Molecular docking results for the Lopinavir using Schrödinger suite 2017-1. Figure 2 shows that the Ganciclovir compound has a H-Bond with the residue ARG553 with a length of 1.58Å and ASP452 with a length of 1.62Å. Also, this compound has two H-bonds with the residue ASP760 with lengths of 1.59Å and 1.63Å, respectively. Figure 2. Molecular docking results for the Ganciclovir using Schrödinger suite 2017-1. Figure 3 shows that the Insoine compound has a H-bond with the residue ASP760 with a length of 1.65Å, with the residue ARG553 have two H-bonds with lengths of 1.58Å and 1.61Å, respectively. Finally, it compounds have a H-bond with a length of 1.48Å. Figure 3. Molecular docking results for the Insoine using Schrödinger suite 2017-1. The Fosamprenavir compound has two a π–π stacking interactions with the residue ARG624 with a length of 1.62Å, another interaction with the residue ARG553 with a length of 1.82Å (see Figure 4 ). Also have a H-bond with a residue ARG553 with a length of 1.62Å, another H-bond with ARG624 with a length of 1.57Å and with the residue THR556 with a length of 1.61Å. Figure 4. Molecular docking results for the Fosamprenavir using Schrödinger suite 2017-1. Ritonavir has a -H bond with the residues LYS298 and LYS621 with a length of 1.26Å and 1.43Å ( Figure 5 ). Also has a H-bond with the residue THR687 with a length 1.13 Å, respectively. Figure 5. Molecular docking results for the Ritonavir using Schrödinger suite 2017-1. Darunavir compound has a π–π stacking interactions with the residue ARG553 with a length of 1.41Å (as can be seen in Figure 6 ). Also have a H-bond with the residue CYS622 with a length 1.38Å, with the residue LYS621 with a length of 1.68Å and two H-bonds with lengths of 1.48Å and 1.38Å, respectively. Figure 6. Molecular docking results for the Darunavir using Schrödinger suite 2017-1. Figure 7 shows that the Tipranavir compound has a π–π stacking interactions with three H-bonds with the residue CYS622 with a length of 1.66Å, with a residue LYS621 with a length of 1.63Å and a π–π stacking interactions with length of 1.46Å. Figure 7. Molecular docking results for the Tipranavir using Schrödinger suite 2017-1. Ganciclovir compound has two π–π stacking interactions with the residue ARG553 with lengths of 1.52Å and 1.61Å (see Figure 8 ). On the other hand, it compounds have a H-bond with the residue CYS622 with a length of 1.58Å and two H-bonds with the residue ASP760 with lengths of 1.61Å and 1.71Å, respectively. Figure 8. Molecular docking results for the Ganciclovir using Schrödinger suite 2017-1. The Molecular docking results for Dolutegravir (see Figure 9 ) involves a π–π stacking interactions with lengths of 1.64Å and two H-bonds with the residues LYS551 and ARG553 with lengths of 1.57Å and 1.59Å, respectively. Figure 9. Molecular docking results for the Dolutegravir using Schrödinger suite 2017-1. Molecular quantum similarity In the Table 1 we can see the structural similarity results for the molecular reaction set. This analysis was developed with the aim the find the common features along the reaction set. From structural point of view the Darunavir (Daru), Dexamethasona (Dexame), Dolutegravir (Dolu), Fosamprenavir (Fosam), Ganciclovir (Gan), Insoine (Inso), Lopinavir (Lop), Ritonavir (Rito) and Tipranavir (Tipra) were analysed, the highest overlap similarity is between the compounds Fosam and Daru (0.343) with a Euclidean distance of 6.946 (see Table 2 ); Lop vs Fosam (0.414) with a Euclidean distance of 6.694 and Inso vs Gan (0.510) with a Euclidean distance of 0.510. These low values obtained are related with steric effects between structures. Additionally, they do not have a skeleton in common and substitutes groups have hight differences. Table 1. Molecular quantum similarity indices using overlap descriptors ( Equation 6 ). O_Hab Daru Dexame Dolu Fosam Gan Inso Lop Rito Tipra Daru 1.000 Dexame 0.247 1.000 Dolu 0.191 0.271 1.000 Fosam 0.343 0.280 0.199 1.000 Gan 0.298 0.324 0.254 0.286 1.000 Inso 0.248 0.239 0.317 0.248 0.510 1.000 Lop 0.322 0.314 0.179 0.414 0.367 0.192 1.000 Rito 0.276 0.336 0.261 0.243 0.257 0.178 0.293 1.000 Tipra 0.242 0.212 0.271 0.234 0.264 0.237 0.149 0.229 1.000 Table 2. Molecular quantum similarity indices using Euclidean distances and overlap descriptor (Equation 11). O_Dab Daru Dexame Dolu Fosam Gan Inso Lop Rito Tipra Daru 0.000 Dexame 6.855 0.000 Dolu 7.347 6.533 0.000 Fosam 6.946 6.871 7.477 0.000 Gan 5.905 5.216 5.786 6.153 0.000 Inso 6.503 6.009 5.979 6.686 4.039 0.000 Lop 7.059 6.713 7.565 6.694 5.866 6.914 0.000 Rito 7.454 6.779 7.354 7.765 6.468 7.168 7.504 0.000 Tipra 7.625 7.367 7.301 7.813 6.445 6.925 8.233 7.992 0.000 Due to the low indices of structural similarity, the electronic similarity has been calculated (see Table 2 ). These values highest values for electronic similarity are Fosam vs Dexame (0.884) with a Euclidean distance of 36.295; Rito vs Dexame (0.896) with a Euclidean distance of 43.347 (see Table 4 ), Lop vs Fosam (0.915) with a Euclidean distance of 33.223; and Rito vs Lop (0.881) with a Euclidean distance of 41.726. Unlike the values of structural similarity, the values of electronic similarity are above of 0.5. These values are supported with the Euclidean distances. We think that the structures, despite being structurally different, are electronically very similar. Reactivity analysis and Fukui function comparison Since the electronic similarity indices (see Tables 3 and 4 ) are higher than the structural ones, this section deepens on the electronic effects associated with the highest values of electronic similarity. In the previous section we have studied which ligands have greater structural and electronic similarity. To continue this analysis, from the point of view of chemical reactivity, several ligand pairs have been selected from those with indices indicating greater electronic and structural similarity. Table 5 shows the global parameters chemical potential, chemical hardness, lobal S softness and global electrophilicity that have been calculated in order to compare the chemical reactivity of these ligands, analysing the values of this table it can be concluded that Insoine, Ganciclovir and Fosamprenavir have a set of parameters that are closer to each other. Since the analysis of the global parameters is limited, we will complete it with the comparison of some local descriptor functions. The electrophile and nucleophile Fukui functions (as a measure of reactivity) are then compared using the Frontier Molecular Orbital (FMO) approach. The electrophilic-nucleophilic character of the following functions also shows those molecular areas that are most likely to form charge-donating interactions (basically by charge delocalisation). These types of interactions are important and are difficult to determine using docking analysis. Table 3. Molecular quantum similarity indices using Coulomb descriptor (Equation 7). C_Hab Daru Dexame Dolu Fosam Gan Inso Lop Rito Tipra Daru 1.000 Dexame 0.796 1.000 Dolu 0.746 0.736 1.000 Fosam 0.831 0.884 0.734 1.000 Gan 0.588 0.812 0.678 0.622 1.000 Inso 0.642 0.796 0.723 0.562 0.861 1.000 Lop 0.876 0.829 0.750 0.915 0.808 0.732 1.000 Rito 0.820 0.896 0.787 0.816 0.688 0.667 0.881 1.000 Tipra 0.794 0.747 0.765 0.853 0.736 0.717 0.616 0.763 1.000 Table 4. Molecular quantum similarity indices using Euclidean distance and Coulomb descriptor (Equation 11). C_Dab Daru Dexame Dolu Fosam Gan Inso Lop Rito Tipra Daru 0.000 Dexame 43.566 0.000 Dolu 48.063 42.659 0.000 Fosam 43.088 36.295 51.575 0.000 Gan 58.487 36.505 42.733 60.307 0.000 Inso 55.233 36.121 40.086 62.719 21.878 0.000 Lop 39.673 46.948 54.617 33.223 57.091 58.720 0.000 Rito 50.153 43.347 55.115 50.812 67.829 67.030 41.726 0.000 Tipra 48.143 51.301 49.703 41.523 56.037 55.175 70.071 57.583 0.000 Table 5. Global chemical reactivity indices (in eV) for some selected ligands. Compounds Chemical Potential ( μ ), eV Chemical Hardness ( ɳ ), eV Softness ( S ), eV Electrophilicity ( ω ), eV Insoine -3.92 5.22 0.192 1.47 Ganciclovir -3.51 5.24 0.191 1.18 Lopinavir -3.57 5.90 0.169 1.08 Fosamprenavir -3.99 5.24 0.191 1.52 Darunavir -3.68 5.28 0.189 1.28 Dexamethasone -4.38 4.87 0.205 1.97 Ritonavir -3.66 5.46 0.183 1.23 Figures 10 and 11 show the Fukui f − ( r → ) and f + ( r → ) functions corresponding to the Insoine and Ganciclovir ligands. Figure 10 shows a strong similarity between the two functions, which may indicate that both ligands have a similar nucleophilic behaviour and/or that they have a similar tendency to donate electronic charge. On the other hand, Figure 11 shows significantly different descriptor functions so we would expect different electrophilic behaviour for these ligands and/or a very different tendency in relation to the possible charge-withdrawing interactions. The Fukui Functions maps were obtained using Highest Occupied Molecular Oribital (HOMO) maps and the Lowest Unoccupied Molecular Orbital (LUMO) maps). Figure 10. Fukui function f − ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | HOMO ( r → ) | 2 ) for the ligands Insoine (left) and Ganciclovir (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Figure 11. Fukui function f + ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | LUMO ( r → ) | 2 ) for the ligands Insoine (left) and Ganciclovir (right). Isovalue: 0.002 in both cases. Figures 12 and 13 show the Fukui functions for the ligands Lopinavir and Fosamprenavir. In Figure 12 it can be seen that there is no similarity between the two functions, indicating that the ligands have different nucleophilic behaviour and/or show a different trend in electronic charge donation. On the other hand, Figure 13 shows descriptor functions with a certain resemblance so we would expect comparable electrophilic behaviour between these ligands although the similarity is moderate. Figure created using Schrödinger suite 2017-1. Figure 12. Fukui function f − ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | HOMO ( r → ) | 2 ) for the ligands Lopinavir (left) and Fosamprenavir (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Figure 13. Fukui function f + ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | LUMO ( r → ) | 2 ) for the ligands Lopinavir (left) and Fosamprenavir (right). Isovalue: 0.002 in both cases. Figures 14 and 15 show the Fukui functions for the ligands Fosamprenavir and Darunavir. Figure 14 shows a strong similarity between the two functions, which may indicate that both ligands have a similar nucleophilic behaviour and/or that they have a similar tendency to donate electronic charge. On the other hand, Figure 15 shows very similar descriptor functions so we would expect comparable electrophilic behaviour between these ligands. Figure created using Schrödinger suite 2017-1. Figure 14. Fukui function f − ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | HOMO ( r → ) | 2 ) for the ligands Fosamprenavir (left) and Darunavir (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Figure 15. Fukui function f + ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | LUMO ( r → ) | 2 ) for the ligands Fosamprenavir (left) and Darunavir (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Figures 16 and 17 show the Fukui functions for the ligands Fosamprenavir and Dexamethasone. In Figure 16 it can be seen that there is no similarity between the two functions, indicating that the ligands have different nucleophilic behaviour and/or show a different trend in electronic charge donation. On the other hand, Figure 17 shows descriptor functions with a certain resemblance so we would expect comparable electrophilic behaviour between these ligands although the similarity is moderate. Figure 16. Fukui function f − ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | HOMO ( r → ) | 2 ) for the ligands Fosamprenavir (left) and Dexamethasona (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Figure 17. Fukui function f + ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | LUMO ( r → ) | 2 ) for the ligands Fosamprenavir (left) and Dexamethasona (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Figures 18 and 19 show the Fukui functions for the ligands Ritonavir and Dexamethasone. In Figure 18 it can be clearly seen that there is no similarity between the two functions, so we think that these ligands have different nucleophilic behaviour. On the other hand, Figure 19 shows descriptor functions with a certain resemblance, so we would expect comparable electrophilic behaviour between these ligands, although the resemblance is very limited. Figure 18. Fukui function f − ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | HOMO ( r → ) | 2 ) for the ligands Ritonavir (left) and Dexamethasona (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Figure 19. Fukui function f + ( r → ) calculated under the Frontier Molecular Orbital (FMO) approximation ( | LUMO ( r → ) | 2 ) for the ligands Ritonavir (left) and Dexamethasona (right). Isovalue: 0.002 in both cases. Figure created using Schrödinger suite 2017-1. Conclusions In this study, the series of compounds, namely Darunavir (Daru), Dexamethasone (Dexame), Dolutegravir (Dolu), Fosamprenavir (Fosam), Ganciclovir (Gan), Insoine (Inso), Lopinavir (Lop), Ritonavir (Rito) and Tipranavir (Tipra), used against SARS-CoV-2 in vitro studies, have been analysed by molecular docking, molecular quantum similarity and chemical reactivity indices to study their active site stabilisation interactions from a structural and electronic point of view. From the molecular docking results, it was observed that Lopinavir, Ganciclovir, Insoin, Fosamprenavir, Ritonavir, Tipranavir, Ganciclovir and Dolutegravir show good active site stabilisation with at least one -H bond in each conformation. To further investigate the active site stabilisation of each ligand, a density functional theory (DFT) analysis of quantum similarity and reactivity was developed. From the structural point of view, the highest overlap similarity is between the compounds Fosam vs Daru (0.343), Lop vs Fosam (0.414) and Inso vs Gan (0.510). From the electronic point of view, the highest Coulomb similarity is between the compounds Fosam vs Dexame (0.884); Rito vs Dexame (0.896), Lop vs Fosam (0.915) and Rito vs Lop (0.881). Finally, with these comparisons, chemical reactivity analysis was performed from a global and local point of view. These Fukui functions were related to charge-donation interactions. Data availability Underlying data Protein Data Bank: SARS-CoV-2 RNA-dependent RNA polymerase. Accession number 6M71; https://www.rcsb.org/structure/6M71 . Harvard Dataverse: Replication data for Study of a series of ligands used as inhibitors of the SARS-CoV-2 virus. https://doi.org/10.7910/DVN/7KFPUT . 59 This project contains the following underlying data: - Optimized structure of Darunavir (Daru). - Optimized structure of Dexamethasona (Dexame). - Optimized structure of Dolutegravir (Dolu). - Optimized structure of Fosamprenavir (Fosam). - Optimized structure of Ganciclovir (Gan). - Optimized structure of Insoine (Inso). - Optimized structure of Lopinavir (Lop). - Optimized structure of Ritonavir (Rito). - Optimized structure of Tipranavir (Tipra). Each structure has the following file extensions: - .out (output file of Gaussian 09 calculations). - .chk (output file of the Gaussian 09 calculations used to generate the contour maps). - .gif (input file of the Gaussian 09 calculations). - .gif.bak (the Gaussian 09 file used to generate the contour maps, i.e. the Highest Occupied Molecular Oribital [HOMO] maps and the Lowest Unoccupied Molecular Orbital [LUMO] maps). - .mol2 (input file for Schrödinger used to generate the docking results). The Gaussian 09 files can be opened by readers using a non-proprietary software, such as ORCA, mentioned previously in the methods. The input files were obtained using Gaussview 6.1, the visualization program of Gaussian 09. Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Acknowledgements AMB thanks Fundación Universitaria Tecnológico Comfenalco. References 1. 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Morales-Bayuelo A, Vivas-Reyes R: Topological model to quantify the global reactivity indexes as local in Diels–Alder reactions, using density function theory (DFT) and local quantum similarity (LQS). J. Math. Chem. 2013; 51 : 125–143. Publisher Full Text 42. Morales-Bayuelo A, Vivas-Reyes R: Theoretical model for the polarization molecular and Hückel treatment of PhosphoCyclopentadiene in an external electric field: Hirschfeld study. J. Math. Chem. 2013; 51 : 1835–1852. Publisher Full Text 43. Morales-Bayuelo A, Baldiris R, Vivas-Reyes R: Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT). J. Theor. Chem. 2013; 2013 (13): 1. Publisher Full Text 44. 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[dataset]. Harvard Dataverse. 2023; V1 . Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 14 Jun 2023 ADD YOUR COMMENT Comment Author details Author details 1 Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia 2 Department of Chemistry-Physics, Science Faculty, Río San Pedro University Campus, Cádiz University, Cádiz, Spain Alejandro Morales-Bayuelo Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Jesús Sánchez-Márquez Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This work was supported by Fundación Universitaria Tecnológico Comfenalco, grant number CIPTEC-2022-I, awarded to Alejandro Morales-Bayuelo. 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: 06 Feb 2024, 12:669 https://doi.org/10.12688/f1000research.127061.2 version 1 Published: 14 Jun 2023, 12:669 https://doi.org/10.12688/f1000research.127061.1 Copyright © 2024 Morales-Bayuelo A and Sánchez-Márquez J. 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 Morales-Bayuelo A and Sánchez-Márquez J. Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.12688/f1000research.127061.2 ) 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 06 Feb 2024 Revised Views 0 Cite How to cite this report: Sehrawat S. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r449741 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v2#referee-response-449741 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 04 Feb 2026 Sharvan Sehrawat , Biological science, Indian Institute of Science Education and Research Mohali, Mohali, Punjab, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.161311.r449741 While the preliminary in-silico data is valuable, it has to be supported by biological analysis. One can easily find interactions using in-silico analysis but the physiological relevance of such data is questionable. Without such analyses, the enthusiasm remains always low ... Continue reading READ ALL While the preliminary in-silico data is valuable, it has to be supported by biological analysis. One can easily find interactions using in-silico analysis but the physiological relevance of such data is questionable. Without such analyses, the enthusiasm remains always low in interpreting such data. The authors should atleast highlight this point in the conclusion/discussion so that data is not over interpreted. 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? Partly 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? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: VIral Immunology and Immunopathology 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 Sehrawat S. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r449741 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v2#referee-response-449741 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: Abdalla M. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r207390 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v2#referee-response-207390 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 04 Feb 2025 Mohnad Abdalla , Shandong University, Jinan, Shandong, China Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.161311.r207390 Scope and Depth of Analysis The study focuses solely on in-silico approaches, including molecular docking, molecular dynamics (MD), and QSAR studies. While these methods are valuable for preliminary investigations, the analysis lacks sufficient depth and comprehensiveness to support strong ... Continue reading READ ALL Scope and Depth of Analysis The study focuses solely on in-silico approaches, including molecular docking, molecular dynamics (MD), and QSAR studies. While these methods are valuable for preliminary investigations, the analysis lacks sufficient depth and comprehensiveness to support strong conclusions. Molecular Dynamics (MD) Limitations The MD simulation was conducted for only 100 ns, which is insufficient to conclusively determine the stability of the protein-ligand complex. Prolonged simulations, typically in the range of 200–500 ns, are necessary to provide a more reliable insight into binding stability and interaction patterns. Validation Concerns A critical issue with the manuscript is the absence of experimental validation. In-silico findings, while valuable, must be corroborated with laboratory studies to ensure biological relevance and reliability. Without experimental data, the conclusions remain speculative and lack practical applicability. Insufficient Analysis of Protein-Ligand Stability The parameters assessed in the MD and QSAR studies are not sufficient to convincingly demonstrate the stability and efficacy of the protein-ligand complex. Additional analyses, such as free energy calculations and more extensive binding interaction studies, would strengthen the findings. Significance and Practical Relevance The study does not provide a clear pathway to translate the in-silico findings into a meaningful biological or therapeutic context. This diminishes its overall impact and relevance. Recommendation Given the above concerns, especially the lack of experimental validation and insufficient MD analysis, I recommend rejecting the manuscript in its current form. The authors are encouraged to conduct complementary laboratory experiments and provide more robust in-silico data before resubmitting to a journal. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? No Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: structural biology, computational modeling, and biopharmaceutical research. 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 Abdalla M. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r207390 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v2#referee-response-207390 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: Dalal V. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r300998 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v2#referee-response-300998 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 16 Jul 2024 Vikram Dalal , Washington University School of Medicine, Saint Louis, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.161311.r300998 The manuscript entitled “Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches” provides crucial insight into chemical reactivity and similarities of a set ... Continue reading READ ALL The manuscript entitled “Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches” provides crucial insight into chemical reactivity and similarities of a set of reported molecules for RdRP of SARS-CoV-2 using in-silico techniques. The authors' work, which includes molecular docking and quantum mechanics to explore the role of stabilization interactions among protein-ligand complexes, is important to our field. While the manuscript is well-written and the work is performed systematically, a few concerns must be addressed. I recommend a major revision and the following suggestions are essential to enhance the quality of the manuscript: 1. In the Molecular docking section of Methods, it's crucial to provide details like charges on protein and ligands, grid box size, grid box dimensions, amino acid residues considered for grid generation and number of poses generated during molecular docking. This information is essential for the reader to understand the methodology and results. Authors can refer to the following articles for further details: - (Dhankhar et al.,2020)(Ref-1); (kumari et al.,2022)(Ref-2) 2. Figures 1 to 9 of the molecular docking illustrations require revisions to highlight the representation and labeling of amino acid residues clearly. Additionally, the figure captions need to be modified to include descriptions of the types and colors designated for the protein, ligand, and interactions. For guidance on these modifications, authors can refer to the cited articles detailing the enhancements of molecular docking figures and captions: - ( (Dhankhar et al.,2020)(Ref-1);kumari et al.,2022)(Ref-2) ) 3. It would be beneficial for authors to provide figures representing the energy gaps of HOMO and LUMO to facilitate the analysis of molecular reactivity. Understanding and comparing HOMO and LUMO plots for ligands can be challenging. For additional details on HOMO and LUMO figures, authors can refer to the following article.": - (Dalal et al.,2021)(Ref-3) 4. The authors thoroughly investigated a crucial topic regarding the potential inhibitor for SARS-CoV-2 using in-silico techniques. It is important to note that they have yet to delve into the potential candidates identified for SARS-CoV-2 using structure-based drug design. The subsequent articles provided comprehensive reports on the potent molecules by targeting various essential elements of SARS-CoV-2.:- (Kumar et al.,2021)(Ref-4);(Dhankhar et al.,2021)(Ref-5); (Dhankhar et al.,2020)(Ref-1)(kumari et al.,2022)(Ref-2) 5. Ensure that the manuscript undergoes thorough screening to correct any typos and grammatical errors. 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? 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? Partly References 1. Dhankhar P, Dalal V, Singh V, Tomar S, et al.: Computational guided identification of novel potent inhibitors of N-terminal domain of nucleocapsid protein of severe acute respiratory syndrome coronavirus 2. J Biomol Struct Dyn . 2022; 40 (9): 4084-4099 PubMed Abstract | Publisher Full Text 2. Kumari R, Kumar V, Dhankhar P, Dalal V: Promising antivirals for PLpro of SARS-CoV-2 using virtual screening, molecular docking, dynamics, and MMPBSA. J Biomol Struct Dyn . 2023; 41 (10): 4650-4666 PubMed Abstract | Publisher Full Text 3. Dalal V, Dhankhar P, Singh V, Singh V, et al.: Structure-Based Identification of Potential Drugs Against FmtA of Staphylococcus aureus: Virtual Screening, Molecular Dynamics, MM-GBSA, and QM/MM. Protein J . 2021; 40 (2): 148-165 PubMed Abstract | Publisher Full Text 4. Kumar KA, Sharma M, Dalal V, Singh V, et al.: Multifunctional inhibitors of SARS-CoV-2 by MM/PBSA, essential dynamics, and molecular dynamic investigations. J Mol Graph Model . 2021; 107 : 107969 PubMed Abstract | Publisher Full Text 5. Dhankhar P, Dalal V, Kumar V: Screening of Severe Acute Respiratory Syndrome Coronavirus 2 RNA-Dependent RNA Polymerase Inhibitors Using Computational Approach. J Comput Biol . 2021; 28 (12): 1228-1247 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Structure Biology, Structure based drug designing, Protein X-Ray crystallography, Cryo Electron Microscopy, Infectious disease, Ion channels, 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 Dalal V. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r300998 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v2#referee-response-300998 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 14 Jun 2023 Views 0 Cite How to cite this report: Lokhande KB. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r191736 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v1#referee-response-191736 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 13 Dec 2023 Kiran Bharat Lokhande , Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Pune, Maharashtra, India Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.139529.r191736 Comments: To the Authors: Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH ... Continue reading READ ALL Comments: To the Authors: Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH levels used in the methodology. PDB ID Citation: I kindly request that you cite the PDB ID used in this study following the guidelines provided by the RCSB. This will ensure proper attribution of the structural data used in your research. Experimental Depth: The study primarily focuses on molecular docking, which has its limitations. Since a similar study with MD simulation studies was published two years ago, it is advisable to incorporate high-end atomistic simulations to support your docking results and provide additional depth to your research. MD Simulations: To strengthen your findings, consider conducting at least 1 microsecond MD simulations in triplicate. This will help validate the outcomes of your molecular docking experiments. Article Suitability: Given the preliminary nature of the study and the existence of a similar study with MD simulations, I recommend an extensive revision of the article to either provide novel insights or enhance the depth of the research before considering it for publication. To the Editor: I would like to highlight several concerns regarding the manuscript in question: The methodology lacks sufficient detail, particularly regarding the protein preparation process, including the pH levels used. The PDB ID used in the study needs to be cited following RCSB guidelines to ensure proper attribution. The study primarily relies on molecular docking, which may not provide the necessary depth of analysis, especially considering a similar study with MD simulations published two years ago. To address this limitation, the authors should conduct high-end atomistic simulations, such as 1 microsecond MD simulations in triplicate, to strengthen the validity of their findings. In its current form, the article appears to be premature and would benefit from extensive revisions to enhance its suitability for publication. I recommend considering these points in the review process to help the authors improve the quality and depth of their research. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No 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? No Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Expertise in Structural Bioinformatics and Computer-Aided Drug Discovery 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 Lokhande KB. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r191736 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v1#referee-response-191736 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 22 Mar 2024 Alejandro Morales-Bayuelo , Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia 22 Mar 2024 Author Response Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH ... Continue reading Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH levels used in the methodology. Answer: pH 6.2 to 6.8 PDB ID Citation: I kindly request that you cite the PDB ID used in this study following the guidelines provided by the RCSB. This will ensure proper attribution of the structural data used in your research. Answer: PDB ID: 6M71Download ; MMDB ID: 188116 ; PDB Deposition Date: 2020/3/16. Experimental Depth: The study primarily focuses on molecular docking, which has its limitations. Since a similar study with MD simulation studies was published two years ago, it is advisable to incorporate high-end atomistic simulations to support your docking results and provide additional depth to your research. MD Simulations: To strengthen your findings, consider conducting at least 1 microsecond MD simulations in triplicate. This will help validate the outcomes of your molecular docking experiments. Answer: All the docking results were supported by molecular dynamic of 20 ns. To verify the molecular stabilization of the ligands on the active site. Article Suitability: Given the preliminary nature of the study and the existence of a similar study with MD simulations, I recommend an extensive revision of the article to either provide novel insights or enhance the depth of the research before considering it for publication. Answer: The article was revised. Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH levels used in the methodology. Answer: pH 6.2 to 6.8 PDB ID Citation: I kindly request that you cite the PDB ID used in this study following the guidelines provided by the RCSB. This will ensure proper attribution of the structural data used in your research. Answer: PDB ID: 6M71Download ; MMDB ID: 188116 ; PDB Deposition Date: 2020/3/16. Experimental Depth: The study primarily focuses on molecular docking, which has its limitations. Since a similar study with MD simulation studies was published two years ago, it is advisable to incorporate high-end atomistic simulations to support your docking results and provide additional depth to your research. MD Simulations: To strengthen your findings, consider conducting at least 1 microsecond MD simulations in triplicate. This will help validate the outcomes of your molecular docking experiments. Answer: All the docking results were supported by molecular dynamic of 20 ns. To verify the molecular stabilization of the ligands on the active site. Article Suitability: Given the preliminary nature of the study and the existence of a similar study with MD simulations, I recommend an extensive revision of the article to either provide novel insights or enhance the depth of the research before considering it for publication. Answer: The article was revised. Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 22 Mar 2024 Alejandro Morales-Bayuelo , Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia 22 Mar 2024 Author Response The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among ... Continue reading The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn't exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. The human body maintains various pH levels in different parts, and this plays a role in the virus's ability to infect cells. For example: Respiratory Tract: The virus primarily enters the body through the respiratory tract. The pH levels in the respiratory tract can vary, and some studies suggest that certain viruses, including coronaviruses, might be influenced by these pH levels. However, the exact relationship is complex and may not be the sole determinant of infection. Cellular Environment: Once the virus enters human cells, the pH of the cellular environment becomes crucial. Inside cells, the virus needs to release its genetic material and replicate. The pH within cellular compartments can affect these processes. Immune Response: The body's immune response also involves pH-dependent processes. Immune cells often function optimally within specific pH ranges, and any disruption might influence the ability of the immune system to combat the virus. It's important to emphasize that pH is just one of many factors influencing viral infections, and the interplay of these factors is intricate. Factors like temperature, humidity, and the overall health of an individual also contribute to the susceptibility and severity of viral infections. The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn't exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. The human body maintains various pH levels in different parts, and this plays a role in the virus's ability to infect cells. For example: Respiratory Tract: The virus primarily enters the body through the respiratory tract. The pH levels in the respiratory tract can vary, and some studies suggest that certain viruses, including coronaviruses, might be influenced by these pH levels. However, the exact relationship is complex and may not be the sole determinant of infection. Cellular Environment: Once the virus enters human cells, the pH of the cellular environment becomes crucial. Inside cells, the virus needs to release its genetic material and replicate. The pH within cellular compartments can affect these processes. Immune Response: The body's immune response also involves pH-dependent processes. Immune cells often function optimally within specific pH ranges, and any disruption might influence the ability of the immune system to combat the virus. It's important to emphasize that pH is just one of many factors influencing viral infections, and the interplay of these factors is intricate. Factors like temperature, humidity, and the overall health of an individual also contribute to the susceptibility and severity of viral infections. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 22 Mar 2024 Alejandro Morales-Bayuelo , Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia 22 Mar 2024 Author Response Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH ... Continue reading Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH levels used in the methodology. Answer: pH 6.2 to 6.8 PDB ID Citation: I kindly request that you cite the PDB ID used in this study following the guidelines provided by the RCSB. This will ensure proper attribution of the structural data used in your research. Answer: PDB ID: 6M71Download ; MMDB ID: 188116 ; PDB Deposition Date: 2020/3/16. Experimental Depth: The study primarily focuses on molecular docking, which has its limitations. Since a similar study with MD simulation studies was published two years ago, it is advisable to incorporate high-end atomistic simulations to support your docking results and provide additional depth to your research. MD Simulations: To strengthen your findings, consider conducting at least 1 microsecond MD simulations in triplicate. This will help validate the outcomes of your molecular docking experiments. Answer: All the docking results were supported by molecular dynamic of 20 ns. To verify the molecular stabilization of the ligands on the active site. Article Suitability: Given the preliminary nature of the study and the existence of a similar study with MD simulations, I recommend an extensive revision of the article to either provide novel insights or enhance the depth of the research before considering it for publication. Answer: The article was revised. Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH levels used in the methodology. Answer: pH 6.2 to 6.8 PDB ID Citation: I kindly request that you cite the PDB ID used in this study following the guidelines provided by the RCSB. This will ensure proper attribution of the structural data used in your research. Answer: PDB ID: 6M71Download ; MMDB ID: 188116 ; PDB Deposition Date: 2020/3/16. Experimental Depth: The study primarily focuses on molecular docking, which has its limitations. Since a similar study with MD simulation studies was published two years ago, it is advisable to incorporate high-end atomistic simulations to support your docking results and provide additional depth to your research. MD Simulations: To strengthen your findings, consider conducting at least 1 microsecond MD simulations in triplicate. This will help validate the outcomes of your molecular docking experiments. Answer: All the docking results were supported by molecular dynamic of 20 ns. To verify the molecular stabilization of the ligands on the active site. Article Suitability: Given the preliminary nature of the study and the existence of a similar study with MD simulations, I recommend an extensive revision of the article to either provide novel insights or enhance the depth of the research before considering it for publication. Answer: The article was revised. Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 22 Mar 2024 Alejandro Morales-Bayuelo , Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia 22 Mar 2024 Author Response The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among ... Continue reading The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn't exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. The human body maintains various pH levels in different parts, and this plays a role in the virus's ability to infect cells. For example: Respiratory Tract: The virus primarily enters the body through the respiratory tract. The pH levels in the respiratory tract can vary, and some studies suggest that certain viruses, including coronaviruses, might be influenced by these pH levels. However, the exact relationship is complex and may not be the sole determinant of infection. Cellular Environment: Once the virus enters human cells, the pH of the cellular environment becomes crucial. Inside cells, the virus needs to release its genetic material and replicate. The pH within cellular compartments can affect these processes. Immune Response: The body's immune response also involves pH-dependent processes. Immune cells often function optimally within specific pH ranges, and any disruption might influence the ability of the immune system to combat the virus. It's important to emphasize that pH is just one of many factors influencing viral infections, and the interplay of these factors is intricate. Factors like temperature, humidity, and the overall health of an individual also contribute to the susceptibility and severity of viral infections. The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn't exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. The human body maintains various pH levels in different parts, and this plays a role in the virus's ability to infect cells. For example: Respiratory Tract: The virus primarily enters the body through the respiratory tract. The pH levels in the respiratory tract can vary, and some studies suggest that certain viruses, including coronaviruses, might be influenced by these pH levels. However, the exact relationship is complex and may not be the sole determinant of infection. Cellular Environment: Once the virus enters human cells, the pH of the cellular environment becomes crucial. Inside cells, the virus needs to release its genetic material and replicate. The pH within cellular compartments can affect these processes. Immune Response: The body's immune response also involves pH-dependent processes. Immune cells often function optimally within specific pH ranges, and any disruption might influence the ability of the immune system to combat the virus. It's important to emphasize that pH is just one of many factors influencing viral infections, and the interplay of these factors is intricate. Factors like temperature, humidity, and the overall health of an individual also contribute to the susceptibility and severity of viral infections. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Carbó-Dorca R. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r178627 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v1#referee-response-178627 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 12 Dec 2023 Ramon Carbó-Dorca , Institute of Computational Chemistry and Catalysis, University of Girona, Girona, Spain Approved VIEWS 0 https://doi.org/10.5256/f1000research.139529.r178627 This study presents in an original way a well-structured study of inhibitors of the COVID virus. The authors give a balanced point of view of the problem using several techniques, among others, quantum similarity analysis. I have been ... Continue reading READ ALL This study presents in an original way a well-structured study of inhibitors of the COVID virus. The authors give a balanced point of view of the problem using several techniques, among others, quantum similarity analysis. I have been impressed with the amount of work implemented in the paper. I will suggest the publication without changes, except for an editorial revision of the text, just in case there are some incorrections that this referee has not been able to detect. 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 Competing Interests: No competing interests were disclosed. Reviewer Expertise: Essentially: Quantum Similarity 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 Carbó-Dorca R. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r178627 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v1#referee-response-178627 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: Metwaly A. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r207285 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v1#referee-response-207285 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 22 Nov 2023 Ahmed Metwaly , Al-Azhar University, Cairo, Egypt Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.139529.r207285 I have thoroughly reviewed the manuscript entitled "Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches" submitted to F1000Research. The ... Continue reading READ ALL I have thoroughly reviewed the manuscript entitled "Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches" submitted to F1000Research. The authors have undertaken a commendable effort to employ molecular mechanics and density functional theory approaches to analyze the ligands' potential as inhibitors of the SARS-CoV-2 virus. However, my primary concern lies in the absence of experimental validation, particularly in vitro studies, to support the computational findings. Despite the availability of the examined compounds and RdRp binding kits, the manuscript lacks crucial experimental data that would enhance the credibility and transnational impact of the study. Experimental validation is essential to confirm the practical applicability of the proposed ligands as SARS-CoV-2 inhibitors. Given the current limitations, I recommend rejecting the manuscript in its present form. I believe that the inclusion of in vitro experimental data would significantly strengthen the study and its potential impact on drug development for COVID-19. I encourage the authors to consider conducting and incorporating such experiments in the next submission. 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? No 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? No Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Drug Discovery 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 Metwaly A. Reviewer Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r207285 ) The direct URL for this report is: https://f1000research.com/articles/12-669/v1#referee-response-207285 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 Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 14 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 4 5 6 Version 2 (revision) 06 Feb 24 read read read Version 1 14 Jun 23 read read read Ahmed Metwaly , Al-Azhar University, Cairo, Egypt Ramon Carbó-Dorca , University of Girona, Girona, Spain Kiran Bharat Lokhande , Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Pune, India Vikram Dalal , Washington University School of Medicine, Saint Louis, USA Mohnad Abdalla , Shandong University, Jinan, China Sharvan Sehrawat , Indian Institute of Science Education and Research Mohali, Mohali, 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 © 2026 Sehrawat S. 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. 04 Feb 2026 | for Version 2 Sharvan Sehrawat , Biological science, Indian Institute of Science Education and Research Mohali, Mohali, Punjab, India 0 Views copyright © 2026 Sehrawat S. 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 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 While the preliminary in-silico data is valuable, it has to be supported by biological analysis. One can easily find interactions using in-silico analysis but the physiological relevance of such data is questionable. Without such analyses, the enthusiasm remains always low in interpreting such data. The authors should atleast highlight this point in the conclusion/discussion so that data is not over interpreted. 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? Partly 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? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise VIral Immunology and Immunopathology 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 (0) Sehrawat S. Peer Review Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r449741) 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/12-669/v2#referee-response-449741 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Abdalla M. 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. 04 Feb 2025 | for Version 2 Mohnad Abdalla , Shandong University, Jinan, Shandong, China 0 Views copyright © 2025 Abdalla M. 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) 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 Scope and Depth of Analysis The study focuses solely on in-silico approaches, including molecular docking, molecular dynamics (MD), and QSAR studies. While these methods are valuable for preliminary investigations, the analysis lacks sufficient depth and comprehensiveness to support strong conclusions. Molecular Dynamics (MD) Limitations The MD simulation was conducted for only 100 ns, which is insufficient to conclusively determine the stability of the protein-ligand complex. Prolonged simulations, typically in the range of 200–500 ns, are necessary to provide a more reliable insight into binding stability and interaction patterns. Validation Concerns A critical issue with the manuscript is the absence of experimental validation. In-silico findings, while valuable, must be corroborated with laboratory studies to ensure biological relevance and reliability. Without experimental data, the conclusions remain speculative and lack practical applicability. Insufficient Analysis of Protein-Ligand Stability The parameters assessed in the MD and QSAR studies are not sufficient to convincingly demonstrate the stability and efficacy of the protein-ligand complex. Additional analyses, such as free energy calculations and more extensive binding interaction studies, would strengthen the findings. Significance and Practical Relevance The study does not provide a clear pathway to translate the in-silico findings into a meaningful biological or therapeutic context. This diminishes its overall impact and relevance. Recommendation Given the above concerns, especially the lack of experimental validation and insufficient MD analysis, I recommend rejecting the manuscript in its current form. The authors are encouraged to conduct complementary laboratory experiments and provide more robust in-silico data before resubmitting to a journal. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? No Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise structural biology, computational modeling, and biopharmaceutical research. 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 (0) Abdalla M. Peer Review Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r207390) 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/12-669/v2#referee-response-207390 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Dalal V. 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. 16 Jul 2024 | for Version 2 Vikram Dalal , Washington University School of Medicine, Saint Louis, USA 0 Views copyright © 2024 Dalal V. 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 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 manuscript entitled “Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches” provides crucial insight into chemical reactivity and similarities of a set of reported molecules for RdRP of SARS-CoV-2 using in-silico techniques. The authors' work, which includes molecular docking and quantum mechanics to explore the role of stabilization interactions among protein-ligand complexes, is important to our field. While the manuscript is well-written and the work is performed systematically, a few concerns must be addressed. I recommend a major revision and the following suggestions are essential to enhance the quality of the manuscript: 1. In the Molecular docking section of Methods, it's crucial to provide details like charges on protein and ligands, grid box size, grid box dimensions, amino acid residues considered for grid generation and number of poses generated during molecular docking. This information is essential for the reader to understand the methodology and results. Authors can refer to the following articles for further details: - (Dhankhar et al.,2020)(Ref-1); (kumari et al.,2022)(Ref-2) 2. Figures 1 to 9 of the molecular docking illustrations require revisions to highlight the representation and labeling of amino acid residues clearly. Additionally, the figure captions need to be modified to include descriptions of the types and colors designated for the protein, ligand, and interactions. For guidance on these modifications, authors can refer to the cited articles detailing the enhancements of molecular docking figures and captions: - ( (Dhankhar et al.,2020)(Ref-1);kumari et al.,2022)(Ref-2) ) 3. It would be beneficial for authors to provide figures representing the energy gaps of HOMO and LUMO to facilitate the analysis of molecular reactivity. Understanding and comparing HOMO and LUMO plots for ligands can be challenging. For additional details on HOMO and LUMO figures, authors can refer to the following article.": - (Dalal et al.,2021)(Ref-3) 4. The authors thoroughly investigated a crucial topic regarding the potential inhibitor for SARS-CoV-2 using in-silico techniques. It is important to note that they have yet to delve into the potential candidates identified for SARS-CoV-2 using structure-based drug design. The subsequent articles provided comprehensive reports on the potent molecules by targeting various essential elements of SARS-CoV-2.:- (Kumar et al.,2021)(Ref-4);(Dhankhar et al.,2021)(Ref-5); (Dhankhar et al.,2020)(Ref-1)(kumari et al.,2022)(Ref-2) 5. Ensure that the manuscript undergoes thorough screening to correct any typos and grammatical errors. 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? 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? Partly References 1. Dhankhar P, Dalal V, Singh V, Tomar S, et al.: Computational guided identification of novel potent inhibitors of N-terminal domain of nucleocapsid protein of severe acute respiratory syndrome coronavirus 2. J Biomol Struct Dyn . 2022; 40 (9): 4084-4099 PubMed Abstract | Publisher Full Text 2. Kumari R, Kumar V, Dhankhar P, Dalal V: Promising antivirals for PLpro of SARS-CoV-2 using virtual screening, molecular docking, dynamics, and MMPBSA. J Biomol Struct Dyn . 2023; 41 (10): 4650-4666 PubMed Abstract | Publisher Full Text 3. Dalal V, Dhankhar P, Singh V, Singh V, et al.: Structure-Based Identification of Potential Drugs Against FmtA of Staphylococcus aureus: Virtual Screening, Molecular Dynamics, MM-GBSA, and QM/MM. Protein J . 2021; 40 (2): 148-165 PubMed Abstract | Publisher Full Text 4. Kumar KA, Sharma M, Dalal V, Singh V, et al.: Multifunctional inhibitors of SARS-CoV-2 by MM/PBSA, essential dynamics, and molecular dynamic investigations. J Mol Graph Model . 2021; 107 : 107969 PubMed Abstract | Publisher Full Text 5. Dhankhar P, Dalal V, Kumar V: Screening of Severe Acute Respiratory Syndrome Coronavirus 2 RNA-Dependent RNA Polymerase Inhibitors Using Computational Approach. J Comput Biol . 2021; 28 (12): 1228-1247 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Structure Biology, Structure based drug designing, Protein X-Ray crystallography, Cryo Electron Microscopy, Infectious disease, Ion channels, 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 (0) Dalal V. Peer Review Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.161311.r300998) 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/12-669/v2#referee-response-300998 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Lokhande K. 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. 13 Dec 2023 | for Version 1 Kiran Bharat Lokhande , Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Pune, Maharashtra, India 0 Views copyright © 2023 Lokhande K. 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 (2) 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 Comments: To the Authors: Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH levels used in the methodology. PDB ID Citation: I kindly request that you cite the PDB ID used in this study following the guidelines provided by the RCSB. This will ensure proper attribution of the structural data used in your research. Experimental Depth: The study primarily focuses on molecular docking, which has its limitations. Since a similar study with MD simulation studies was published two years ago, it is advisable to incorporate high-end atomistic simulations to support your docking results and provide additional depth to your research. MD Simulations: To strengthen your findings, consider conducting at least 1 microsecond MD simulations in triplicate. This will help validate the outcomes of your molecular docking experiments. Article Suitability: Given the preliminary nature of the study and the existence of a similar study with MD simulations, I recommend an extensive revision of the article to either provide novel insights or enhance the depth of the research before considering it for publication. To the Editor: I would like to highlight several concerns regarding the manuscript in question: The methodology lacks sufficient detail, particularly regarding the protein preparation process, including the pH levels used. The PDB ID used in the study needs to be cited following RCSB guidelines to ensure proper attribution. The study primarily relies on molecular docking, which may not provide the necessary depth of analysis, especially considering a similar study with MD simulations published two years ago. To address this limitation, the authors should conduct high-end atomistic simulations, such as 1 microsecond MD simulations in triplicate, to strengthen the validity of their findings. In its current form, the article appears to be premature and would benefit from extensive revisions to enhance its suitability for publication. I recommend considering these points in the review process to help the authors improve the quality and depth of their research. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No 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? No Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Expertise in Structural Bioinformatics and Computer-Aided Drug Discovery 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 (2) Author Response 22 Mar 2024 Alejandro Morales-Bayuelo, Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia Detailed Methodology: It would greatly enhance the reproducibility of your study if you could provide more detailed information regarding the protein preparation process. Specifically, please include information about the pH levels used in the methodology. Answer: pH 6.2 to 6.8 PDB ID Citation: I kindly request that you cite the PDB ID used in this study following the guidelines provided by the RCSB. This will ensure proper attribution of the structural data used in your research. Answer: PDB ID: 6M71Download ; MMDB ID: 188116 ; PDB Deposition Date: 2020/3/16. Experimental Depth: The study primarily focuses on molecular docking, which has its limitations. Since a similar study with MD simulation studies was published two years ago, it is advisable to incorporate high-end atomistic simulations to support your docking results and provide additional depth to your research. MD Simulations: To strengthen your findings, consider conducting at least 1 microsecond MD simulations in triplicate. This will help validate the outcomes of your molecular docking experiments. Answer: All the docking results were supported by molecular dynamic of 20 ns. To verify the molecular stabilization of the ligands on the active site. Article Suitability: Given the preliminary nature of the study and the existence of a similar study with MD simulations, I recommend an extensive revision of the article to either provide novel insights or enhance the depth of the research before considering it for publication. Answer: The article was revised. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Author Response 22 Mar 2024 Alejandro Morales-Bayuelo, Process Research Center of Tecnológico Comfenalco (CIPTEC), Industrial Engineering Program, Fundacion Universitaria Tecnologico Comfenalco, Cartagena, Colombia The influence of pH (acidity or alkalinity) on the SARS-CoV-2 virus, which causes COVID-19, is an interesting topic. However, it's important to note that SARS-CoV-2 primarily infects and spreads among human cells, and the virus itself doesn't exist independently in the environment for long periods. The pH level becomes more relevant when considering how the virus interacts with the human body. The human body maintains various pH levels in different parts, and this plays a role in the virus's ability to infect cells. For example: Respiratory Tract: The virus primarily enters the body through the respiratory tract. The pH levels in the respiratory tract can vary, and some studies suggest that certain viruses, including coronaviruses, might be influenced by these pH levels. However, the exact relationship is complex and may not be the sole determinant of infection. Cellular Environment: Once the virus enters human cells, the pH of the cellular environment becomes crucial. Inside cells, the virus needs to release its genetic material and replicate. The pH within cellular compartments can affect these processes. Immune Response: The body's immune response also involves pH-dependent processes. Immune cells often function optimally within specific pH ranges, and any disruption might influence the ability of the immune system to combat the virus. It's important to emphasize that pH is just one of many factors influencing viral infections, and the interplay of these factors is intricate. Factors like temperature, humidity, and the overall health of an individual also contribute to the susceptibility and severity of viral infections. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Lokhande KB. Peer Review Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r191736) 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/12-669/v1#referee-response-191736 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Carbó-Dorca R. 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. 12 Dec 2023 | for Version 1 Ramon Carbó-Dorca , Institute of Computational Chemistry and Catalysis, University of Girona, Girona, Spain 0 Views copyright © 2023 Carbó-Dorca R. 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 This study presents in an original way a well-structured study of inhibitors of the COVID virus. The authors give a balanced point of view of the problem using several techniques, among others, quantum similarity analysis. I have been impressed with the amount of work implemented in the paper. I will suggest the publication without changes, except for an editorial revision of the text, just in case there are some incorrections that this referee has not been able to detect. 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 Competing Interests No competing interests were disclosed. Reviewer Expertise Essentially: Quantum Similarity 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) Carbó-Dorca R. Peer Review Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r178627) 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/12-669/v1#referee-response-178627 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Metwaly 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. 22 Nov 2023 | for Version 1 Ahmed Metwaly , Al-Azhar University, Cairo, Egypt 0 Views copyright © 2023 Metwaly 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) 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 I have thoroughly reviewed the manuscript entitled "Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches" submitted to F1000Research. The authors have undertaken a commendable effort to employ molecular mechanics and density functional theory approaches to analyze the ligands' potential as inhibitors of the SARS-CoV-2 virus. However, my primary concern lies in the absence of experimental validation, particularly in vitro studies, to support the computational findings. Despite the availability of the examined compounds and RdRp binding kits, the manuscript lacks crucial experimental data that would enhance the credibility and transnational impact of the study. Experimental validation is essential to confirm the practical applicability of the proposed ligands as SARS-CoV-2 inhibitors. Given the current limitations, I recommend rejecting the manuscript in its present form. I believe that the inclusion of in vitro experimental data would significantly strengthen the study and its potential impact on drug development for COVID-19. I encourage the authors to consider conducting and incorporating such experiments in the next submission. 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? No 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? No Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Drug Discovery 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 (0) Metwaly A. Peer Review Report For: Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches [version 2; peer review: 1 approved, 2 approved with reservations, 3 not approved] . F1000Research 2024, 12 :669 ( https://doi.org/10.5256/f1000research.139529.r207285) 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/12-669/v1#referee-response-207285 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 Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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