Rosmarinic acid as a novel biomedical drug for inhibiting the replication of herpes and dengue viruses: An In-silico assessment

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Christy Rani, K. Kalaimathi, S. Jayasree, S Murugesan, Prabhu S, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2122165/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Since ancient times to till now, viruses such as dengue, herpes virus, ebola, AIDS, influenza, ebola, chicken meat and SARS have been roaming around causing great health burdens. To fight against these contagious viruses, people rely heavily on medicinal plants to enhance their immune system of innate and adaptive. In this research, the preparation of ligands and proteins was performed using the Maestro V.13.2 module tool. This software, consisting of LigPrep, Grid Generation, SiteMap and Glide XP, has each contributed significantly to the preparation of ligands and proteins. Ultimately, the research found that (R)-(+)-rosmarinic acid was found to have significant docking scores of -10.847 for herpes virus, of -10.033 for NS5 and − 7.259 for NS1. In addition, the Pass Server prediction indicates that rosmarinic acid possesses a diverse spectrum of enzymatic activities, as Probability Active (Pa) values ​​start at > 0.751; whereas it has fewer adverse effects than the drugs prescribed for viruses. Accordingly, it was found that the rate of acute toxicity values ​​of rosamric acid. According to this analysis, we expect that the current research will reveal a clear route to finding a medicine that can successfully lessen the complications of numerous viruses without causing any harmful effects. Ultimately, we concluded that (R)-(+)-rosmarinic acid would expose significant antiviral effects in in-vitro and in-vivo experiments and also this research would be a valuable asset for future especially those who wish to discover a drug molecule for variety of viruses. Rosmarinic acid Anti-viral drug Biomedical profile Acute Toxicity Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 1. Introduction Viral infections have been a major cause of morbidity and mortality worldwide since the 20th century. In particular, viruses such as dengue, herpes virus, Ebola, AIDS, influenza and SARS are currently roaming the world as pandemics and epidemics (Ben-Shabat et al., 2019). Of concern is that human mortality from dengue and herpes virus infections is significantly increasing. The fact that the number of dengue cases reported to WHO has increased eight-fold over the past 20 years, from 505,430 cases in 2000 to over 2.4 million in 2010 and 5.2 million in 2019 supports this (WHO, 2022). On the other hand, worldwide 491 million people between the ages of 15 and 49 are reported to have HSV-2 infection, while 3.7 billion people under the age of 50 are reported to have HSV-1 infection (WHO, 2022).To fight the virus particles and inhibit their replication in the body, almost ninety types of antiviral drugs are available today, but one drug only control one virus. Similar to these drugs, the classic antiviral drugs such as interferon and ribavirin have antiviral potential against most viruses in in-vitro studies, but often showed no effect in infected people during treatment (Ben-Shabat et al., 2019). Currently prescribed antiviral drugs are expensive, ineffective against some viruses and have harmful side effects on the human body with long-term use. On the other hand, natural substances, especially medicinal plants, have a broad therapeutic potential against a wide variety of infectious diseases caused by microorganisms such as viruses, fungi, bacteria, etc. In India, for example, two polyherbal formulation, Nilavembu Kudineer and Kabasura Kudineer, were have used to boost the immune system during the covid lockdown period. Although viruses pose a health burden to human race, most people currently rely heavily on medicinal plants to stimulate and modulate the immune system against the infectious complications of viruses (Prabhu et al., 2022). After consuming the plant extracts, the phytochemicals unfold their therapeutic potential either alone or in combination with other constituents as synergetic effects. In order to find such a multi-targeting viral drug molecule, the present study aimed to investigate the antiviral potential of (R)-(+)-rosmarinic acid . (R)-(+)-rosmarinic acid (RA) is regarded as a promising phytochemical in the pharmaceutical industry due to its wide range of pharmacological effects (Chunxu et al., 2020 ). It is represented by the chemical formula C 18 H 16 O 8 . It has been found that there are nearly 160 species of plants, including hornworts of bryophytes and angiosperms, both dicots and monocots (Huaquan et al., 2022 ). However, the RA was first discovered and isolated in 1958 in Rosmarinus officinalis L. Therefore, it is being considered as the main source of RA. Later, it was found in significant amounts in Thymus masticina, Ocimum tenuiflorum, Forsythia coriana , and Hyptis pectinate (Gordo et al., 2012 ; Chunxu et al., 2020 ). Because RA is water soluble, previous studies indicate that approximately 90% exhibits its therapeutic potential when even grinding and application with a universal solvent (Fecka, 2007 ). Consistent with this statement, this molecule is being studied for decades in in-silico , in-vitro and in-vivo studies to screen its drug potential against health complications such as CNS diseases, diabetes, oncology and the diseases caused by microorganisms including dengue, herpes viruses, etc. There is currently no adequate treatment for viruses; whereas the drugs available are expensive and have side effects. Therefore, given the lack of antiviral drugs and the versatile pharmacological properties of (R)-(+)-rosmarinic acid, the present research aimed to investigate the antiviral potential of (R)-(+)-rosmarinic acid against dengue and herpes viruses. As it could possess effective antiviral potential to alleviate these viruses related problems. 2. Materials And Methods 2.1. Biological data Initially, (R)-(+)-rosmarinic acid was chosen as a ligand molecule and retrieved from the chemical database to find out its antiviral potential against the proteins of dengue and herpes viruses. Similar to the ligand, the viral proteins were retrieved from the protein database as in crystallographic form to dock with (R)-(+)-rosmarinic acid. The alphanumeric identities of the proteins were 1F5Q, 27JW and 4OIG ( www.rcsb.com ). 2.2. Computational tools In this research, the preparation of ligands and proteins was performed using the Maestro V.13.2 module tool. This software, consisting of LigPrep, Grid Generation, SiteMap and Glide XP, has each contributed significantly to the preparation of ligands and proteins. It ran on the highly configured Centox Linux operating system and was used for further investigation, in line with previous computer studies (Kalaimathi et al., 2022 ; Prabhu et al., 2022). 2.3. Target preparation With the Protein Preparation Wizard module, the proteins of dengue and herpes viruses were adjusted by removing the water molecules from them. In general, the water molecules-containing protein was not compatible for the molecular docking; therefore the water molecules were clean off from the proteins in order to allow for further investigation. Two gears such as preparation and refinement were utilized during this process to detect water molecules and remove them from the proteins, while the workspace analyzer was aided to add the missing residues in the proteins. Later, the proteins were shifted for docking using two more gears: optimization and minimization. The entire target preparation process has been completed in accordance with our previous studies (Christy Rani et al., 2022; Kalaimathi et al., 2022 ). 2.4. Active site prediction This phase is critical in docking as it helps identify the correct putative binding pocket in the target molecules. Although the protein consists of an enormous number of binding sites, only one site could be used to generate a grid box. Therefore, it is chosen after its site volume and values were found to be higher than the other sites detected from this protein. Ultimately, only one site was chosen as a putative ligand binding pocket because of its potential binding metrics for ligand binding (Vijayakumar et al, 2018 ). 2.5. Grid generation The binding site was stabilised as a good place for binding the (R)-(+)-rosmarinic acid by constructing the grid box with the gliding grid module. By constructing the lattice box using glide grid module, the putative binding site was stabilized as a suitable ligand site of (R)-(+)-rosmarinic acid. Prior to switching the molecular dopcking, the binding site was established to study the drug potential of (R)-(+)-rosmarinic acid by knowing the following parameters such as docking scores, binding affinities, etc. With this method, a grid box was constructed in order to dock the phytochemicals at the focal point of the protein within the targets. To fix the ligand binding site in the protein molecules, the grid box was constructed with X: 69.31, Y: 64.39 and Z: -14.86 for 1F5Q; whereas, the grid boxes to dengue viruses were constructed with X: 31.85, Y: 66.9 and Z: 30:43 for 2J7W and X: 38.95, Y: -20.17 and Z: -0.23 for 4UO5 respectively. 2.6. Ligand preparation Before docking with target molecules, the mole format of rosmarinic was prepared using the LigPrep (2.4) module. The Optimized Potentials for Liquid Simulations 2005 (OPLS2005) force field was also used to refine the topology of the detected ligand. Similar to protein preparation, two mechanisms such as tautomers and stereoisomers have been exploited in ligand preparation to reduce the geometric complexity of the ligand. The construction of the rosmarinic as 3D from 1D (smiles) and 2D was accomplished by the ligprep module. Later, the (R)-(+)-rosmarinic acid with a specific molecular weight or with a specific amount and type of functional groups with the appropriate chirality was properly processed and used for further research. 2.7. Molecular docking The successfully prepared ligands and protein molecules were docked in the Xtra Precision Docking Mode. It was used to determine the strength of interactions between viral proteins and (R)-(+)-rosmarinic acid, specifically to know binding affinities and inhibition constants between them. To assess the effectiveness of (R)-(+)-rosmarinic acid as a treatment for these viral complications, docking metrics including docking scores, hydrophobic interactions, hydrogen bonding (side and back chains), pi-pi stacking, and salt bridge contacts were examined (Vijayakumar et al., 2016 ). 2.8. Pharmacophore analysis Structure-based and ligand-based techniques have been integrated into the energetic (e)-pharmacophore approach. The E-Pharmacophore scripting tool, developed to explore the pharmacophore hypothesis of rosmarnic acid. Using the Phase v 3.4 module, the pharmacophore sites of (R)-(+)-rosmarinic acid such as hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic group (H), positively ionizable (P), negatively ionizable (N), and aromatic ring (R) have been discovered. 2.9. Drug probability of Phytochemicals With the help of the pass server, the drug potential of (R)-(+)-rosmarinic acid regard to the probabilities of active and inactive pharmacological properties were explored; whereas, the adverse effects the phytochemical and coneventional drugs were also careened. Using the Gusar, the acute toxicity of (R)-(+)-rosmarinic acid in rats was also noted at different doses of route of administration such as intravenous (IV), intraperitoneal (IP), subcutaneous (SC), and oral (O). (Kalaimathi et al., 2021 ). 3. Results 3.1. Active sites of Viral Proteins To locate the ligand binding region, the appropriate ligand site in the protein molecules was examined. Although the molecules possess numerous sites, the ligand binding sites were filtered based on their site score and volume. Here, this site analysis was revealed the residues consistency of three viral proteins such as 1F5Q, 2J7W and 4OIG. At the radius of 5Aº, the binding site residues of murine gamma herpesvirus cyclin complexed with human cyclin-dependent kinase 2 have been identified as LYS89, ASP86, GLN85, HIE84, LEU83, PHE82, GLU81, PHE80, LEU143, ALA144, ASP145, PHE146, GLY147, GLU51, LYS33, LEU32, ALA31, LEU134, GLN131, VAL64, ILE64 and LEU55. Similarly, at the radius of 3Aº, the the binding site residues of NS5 RNA dependent RNA polymerase domain complexed with 3' dGTP have been identified as PRO319, THR317, PRO258, ASN207, ARG257, LYS211, ALA213, ASP276, PHE277 and ASP278. Furthermore, at the radius of 3Aº, the binding site residues of Flavivirus nonstructural protein 1 (NS1) molecule have been identified as ARG481, VAL450, THR571, LYS575, VAL577, VAL579, VAL358, LYS355, PHE354, TYR299, TRP302, ILE592, GLN602, SER600 and GLY599. Since all interactions with residues begin in this binding cavity, it plays key role in molecular docking exploration. 3.2. Molecular docking In the present insilico apparoach, we examined the compatibility of (R)-(+)-rosmarinic acid with the viral proteins of dengue and herpes viruses. Eventually, we found that the (R)-(+)-rosmarinic acid was a possible drug because it contains better docking metrics for the docked dengue protein, including docking score, electrostatic energy, and hydrogen bonding. Particularly, the docking scores revealed that it posses potential therapeutic effects to combat these viruses. It was additionally proven by the affinities between these molecules such as hydrongen bond, π-π stacking, electrostatic potential, π-cation, etc. It more clearly expresses the contribution and flexibility of the ligand with the docked viral proteins. Moreover, it has been clearly shown reveal as follows. 3.2.1. (R)-(+)-rosmarinic acid with Murine Gamma Herpesvirus Cyclin Complexed to Human Cyclin Dependent Kinase 2 (R)-(+)-rosmarinic acid was found to have a rather impressive docking score of -10.847 with this viral protein (Table 1). In order to examine its inhibitory constant and its binding affinities with murine gamma herpesvirus cyclin complexed with human cyclin-dependent kinase 2, the docked complex was examined (Fig. 1). At the end of the investigation, this research found that (R)-(+)-rosmarinic acid has approximately six hydrogen contact lines with the herpesvirus amino acid residues. Amino acid residues such as PHE146, GLU51 (covalent bond), LYS33, PHE80, LEU83 and HIE84 were found to be in contact with (R)-(+)-rosmarinic acid in significant levels of hydrogen bonding distances (Fig. 2a). GLU51 was known to have covalent bond interactions with (R)-(+)-rosmarinic acid ; the distances of these contacts were measured as 1.47 and 12.06. Moreover, the hydrogen bond contact distances of other residues with (R)-(+)-rosmarinic acid were found as 2.14 in PHE146, 2.13 in LEU83, and 2.14 in HIE84; while the PHE80 was found as π-π stacking contacts (Fig. 2a and Table 2). Figure 2b shows which functional group is involved in hydrogen bonding contacts with (R)-(+)-rosmarinic acid . Except the residues PHE80 and LEU83, all the residues bind with the hydroxyl group (OH) of (R)-(+)-rosmarinic acid . LEU83, on the other hand, was found in contact with oxygen (O). However, PHE80 was found in contact with the main compound of (R)-(+)-rosmarinic acid , known as the pi-pi contact (green line) (Fig. 2b). 3.2.2. (R)-(+)-rosmarinic acid with NS5 RNA dependent RNA polymerase domain complexed with 3' dGTP (R)-(+)-rosmarinic acid was found to have a rather impressive docking score of -10.033 against this viral protein (Table 1). In order to examine its inhibitory constant and its binding affinities with NS5 RNA dependent RNA polymerase domain complexed with 3' dGTP, the docked complex was examined (Fig. 3). At the end of the investigation, this research found that (R)-(+)-rosmarinic acid has approximately four hydrogen contact lines with this viral protein amino acid residue. Amino acid residues such as THR571, VAL450, PHE354 and SER600 were found to be in contact with (R)-(+)-rosmarinic acid in significant levels of hydrogen bonding distances (Fig. 4a). The hydrogen bond contact distances of among these molecules were found as 2.28 in THR571, 2.10 in VAL450, 1.71 in PHE354 and 2.54 in SER600 (Fig. 4a and Table 2). Figure 4b shows which functional group is involved in hydrogen bonding contacts with (R)-(+)-rosmarinic acid. Except the residues SER600, all the residues bind with the hydroxyl group (OH) of (R)-(+)-rosmarinic acid. LEU83, on the other hand, was found in contact with oxygen (O). The contact lines have been shown quite accurately as binding affinities in Figure 2b. 3.2.3. (R)-(+)-rosmarinic acid with Flavivirus nonstructural protein 1 (NS1) (R)-(+)-rosmarinic acid was found to have a rather impressive docking score of -7.259 against this viral protein (Table 1). In order to examine its inhibitory constant and its binding affinities with Flavivirus nonstructural protein 1 (NS1), the docked complex was examined (Fig. 5). At the end of the investigation, this research found that (R)-(+)-rosmarinic acid has approximately five hydrogen contact lines with the herpesvirus amino acid residues. Amino acid residues such as THR317 (Covalent binding), ARG257, LYS211, PHE277 and ASP278 found to be in contact with (R)-(+)-rosmarinic acid in significant levels of hydrogen bonding distances (Fig. 6a). THR317 was known to have covalent bond interactions with (R)-(+)-rosmarinic acid ; the distances of these contacts were measured as 1.96 and 1.92. Moreover, the hydrogen bonding contact distances of other residues with (R)-(+)-rosmarinic acid were found to be 2.76 in PHE277 and 1.92 in ASP278; while LYS211 and ARG257 were found as cation and salt bridge contacts, LYS211 in particular binds covalently with (R)-(+)-rosmarinic acid as a π-cation contact at one end and as a salt bridge contact at another end (Fig. 6a and Table 2). Figure 5b shows which functional group is involved in hydrogen bonding contacts with (R)-(+)-rosmarinic acid. Except the residues LYS211, all the residues bind with the hydroxyl group (OH) of (R)-(+)-rosmarinic acid (Fig. 6b). MM-GBSA In the MM-GBSA validation, the free energy values of (R)-(+)-rosmarinic acid are found to be -58.65 for 1F5Q, -52.17 for 277W and -48.52 for 4OIG (Table. 1). The final results of the investigation imply that (R)-(+)-rosmarinic acid has the strong binding with the docked viral proteins. 3.4. Pharmacophore The data set was divided into active, moderately active and inactive regions by keeping the activity threshold in the 7.2 range. The (R)-(+)-rosmarinic acid binding domain in terms of its five characteristics as shown in Figure 7 included the generic pharmacophore hypotheses due to its high survival value. 3.5. Drug probability active (Pa) and probability inactive (Pi) by Pass server The pass server's prediction showed that (R)-(+)-rosmarinic acid is discovered to have broad pharmacological possibilities as notable Pa score, with a drug probability active score ranging from 0.710 to 0.956. Although (R)-(+)-rosmarinic acid showed broad pharmacological potential, only the most probable pharmacological activities were shown in Table 3. On the other hand, this prediction shows that the side effects of prescribed herpesvirus drugs such as aciclovir, famiciclovir, penciclovir and valaciclovir. Accordingly, the present research suggests that these drugs might lead to further complications for human health after administration as a treatment for the herpes virus (Supplementary Table 1-4). The most significant adverse effects of these drugs were shown in Figure 8-11. 3.6. Rat acute toxicity of (R)-(+)-rosmarinic acid predicted by GUSAR The rate acute toxicity of (R)-(+)-rosmarinic acid was measured by LD50 at log10 (mmol/kg) and LD50 mg/kg levels. The applicability domain models were measured in terms of administration, including intraperitoneal administration (IP), intravenous administration (IV), oral administration (O), and subcutaneous administration (SC). The values of toxicity were clearly shown in Fig.2. 4. Discussion In the present computational research of antiviral drugs, (R)-(+)-rosmarinic acid was found to have remarkable antiviral abilities against the complications related to gamma herpes virus, NS5 RNA-dependent RNA polymerase domain complexed with 3'-dGTP and non-structural protein 1 (NS1) of flavivirus. The present research has recognized that (R)-(+)-rosmarinic acid is an effective antiviral drug for numerous viruses like dengue, herpes virus, etc. This statement was confirmed after evaluating the drug potential of this molecule in terms of binding affinities. Based on the present results, the existence of this molecule in plants and the antiviral potential of this molecule for other viruses have been clearly discussed as follows. Although the molecule was first discovered and isolated from Rosmarinus officinalis L, a recent review reported that (R)-(+)-rosmarinic acid has been widely isolated from many wild and cultivated plants worldwide over the past three decades. Consistent with this statement, plants such as Melissa officinalis , Mentha balsamea Wild, Origanum vulgare , Orthosiphon stamineus , Prunella vulgaris , Salvia officinalis L, Rosmarinus officinalis L, Salvia miltiorrhiza , Thymus vulgaris L and Zataria multiflora are reported to contain significant amounts of rosemary acid. The amounts of rosamarinic acid that scientists have isolated from various plants were listed in Table 1 . To assess the pharmacological potential of this phytochemical, it was tested on different targets in in-silico , in-vitro and in-vivo models. 4.1. Biomedical profiles and immune mechanisms of (R)-(+)-rosmarinic acid Since 1997 to date it has been reported to have various pharmacological properties as a novel candidate for inflammation, antioxidant potential, cancer, diabetic, antiviral potential for zoonotic and non-zoonotic diseases, neurodegenerative, hypertensive, antimicrobial and so on (Noor et al., 2022 ). On the other hand, it has also been used as folk medicine, cosmetics and dietary supplements since ancient times (Baba et al., 2004 ). In 2011, Hsu et al. ( 2011 ) found that (R)-(+)-rosmarinic acid markedly reduced IL-1 and TNF-α release, thereby ameliorating collagen-induced arthritis in in-vivo conditions. These are part of the innate immune system of the human body. The cytokinins such as interferon-1 and TNF-α play a key role in activating the innate immune system. According to the research report of Hsu et al. ( 2011 ), we found that by inducing these two cytokinins, (R)-(+)-rosmarinic acid indirectly activates the innate immune system to protect the human body from harmful materials. 4.2. Antiviral potential of (R)-(+)-rosmarinic acid There are numerous studies demonstrating that (R)-(+)-(R)-(+)-rosmarinic acid has antiviral activity against a variety of viruses including Herpes simplex type 2 virus (Nolkemper et al., 2006 ), Japanese encephalitis virus (JEV) (Swarup et al., 2007 ), herpes simplex type 1 Virus (Ansari-Dogaheh et al., 2013 ), hepatitis B virus (Tsukamoto et al., 2018 ), Enterovirus 71 infection (Lin et al., 2019 ), dengue virus type 2 (Wahab et al., 2018 ), Severe acute coronavirus respiratory syndrome (SARS-CoV) (Wang et al., 2021 ), NS2B47-NS3 dengue virus (Mariya Jancy Rani et al., 2022) and so on. Following this statement, the few studies on the antiviral potential of (R)-(+)-rosmarinic acid are clearly discussed below to demonstrate its drug capability as a multiviral drug candidate. In 2006, a research by Nilkemper et al. (2006) tested the anti-herpes simplex virus on RC-37 cells in a plaque reduction assay using the extracts of Melissa officinalis, Mentha piperita, Prunella Vulgaris and Rosmarinus vulgaris . In all tested extracts, (R)-(+)-rosmarinic acid was clearly identified as one of the most important phytochemicals. Finally, they stated that the extract may have strong antiviral activity against HSV-1 and HSV-2 due to the existence of (R)-(+)-rosmarinic acid in the extracts. On the other hand, a study by Swarup et al. ( 2007 ) reported that (R)-(+)-rosmarinic acid significantly reduced mortality in mice infected with Japanese encephalitis virus (JEV); there it significantly reduced viral loads (P < 0.001) and proinflammatory cytokine levels (P < 0.001) in the mice than can be seen in the untreated mice at 8–9 days post-infection. A study by Ansari-Dogaheh et al. ( 2013 ) reported in 2013 that the (R)-(+)-rosmarinic acid was present in Zhumeria majdae at 1.3% at 50 g ml-1. It was confirmed by them after Zhumeria majdae extracts were treated on HSV-1. Eventually, they proposed that the extracts could be having anti-HSV 1 effect due to the existence of this phytochemical. In 2017, Chen et al. (2017) explored the antiviral potential of Melissa officinalis extracts on EV71 after it was formulated with methanolic solvents. It showed the most remarkable anti-EV71 efficiency, plaque formation, cytopathic effect and viral protein synthesis in EV71-infected cells. They finally isolated (R)-(+)-rosmarinic acid as a biomedical active ingredient from this extract. They later proposed that it reduces viral attachment and entry cleavage of eukaryotic translation initiation factor 4G (eIF4G); generation of reactive oxygen species (ROS); and translocation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) from the nucleus to the cytoplasm. Similarly, at concentrations of 30µg/mL, the (R)-(+)-rosmarinic acid was reduced the EV71 IRES-mediated translation, while viral absorbance states for (R)-(+)-rosmarinic acid had an IC50 of 0.50 mM with a TI of 2.97, according to a Study by Chung et al. (2015). In addition, the 100 mg/mL of (R)-(+)-rosmarinic acid has reduced the formation of EV71 virus particles and VP1 protein, triggering the antiviral efficacy. In 2019, an in-vitro study reported that (R)-(+)-rosmarinic acid possessed potent protective effects against human infection by EV71. Furthermore, it was found to not only protect cells from EV71-induced cytopathic effects, but also from EV71-induced pathogenesis and consequences. Therefore, they proposed that it has been significantly reduce EV71 infection in the early stages (Lin et al., 2019 ). A recent study by Mariya Jancy Rani et al. (2022) indicated that (R)-(+)-rosmarinic acid has a possible therapeutic effect for dengue following their in-silico explorations. Eventually, they were suggested that (R)-(+)-rosmarinic acid could be a potent antiviral candidate for dengue than among the docked polyphenols of their research. 5. Conclusions Viral infections have been one of the major causes of disease and death in human race worldwide. Dengue and herpes viruses in particular cause the worst health problems, sometimes leading to death. In this scenario, there is no adequate treatment to combat these viral particles and complications. Still, people around the world are trying to boost their immune systems by using plants, either alone or as polyherbal formulation, to fight off infectious agents, especially viruses. Therefore, the present research was also aimed to explore the antiviral potential from the pharmacologically versatile phytochemical (R)-(+)-rosmarinic acid. Current research shows that (R)-(+)-rosmarinic acid exhibits impressive hydrogen bonding interactions, strong docking values, and glide energy values. In addition, the pharmacokinetic property assessments have shown that this molecule possesses a variety of pharmacological properties by activating the enzymes of the human body. Accordingly, we believe that when tested in in-vitro and in-vivo experiments, (R)-(+)-rosmarinic acid would reveal drug activity against dengue and herpes virus replication. On the other hand, it has been found to have minimal side effects than the drugs currently prescribed for herpes viruses. Similarly, evaluation of the pharmacokinetic properties had shown that it has less toxicity to rats at doses of LD50 log10 (mmol/kg) and LD50 (mg/kg) by different routes of administration. Today's pharmaceutical sector is trying to discover a novel antiviral drug for many viruses; so far, however, no single drug is sufficient to combat the numerous viruses as a single drug. According to this investigation, we hope that the current research will show a clear way to find a drug that can effectively reduce the complications of various viruses. Declarations Authors Contribution Christy Rani: Investigation, Formal Analysis, Original Draft Writing, Data Maintenance. Kalaimathi: conceptualization, methodology, formal analysis, written review and editing. Jayashree: investigation, formal analysis, validation. Murugesan: Investigation, Formal Analysis. Prabhu: conceptualization, methodology, review & editing and supervision. Pinkie Cherian: Formal analysis Declaration of Competing Interest None Acknowledgements Each author expresses his gratitude to their institutions for providing the opportunity to do develop this manuscript. The corresponding author expresses his thanks to the management of Annai Vailankanni Arts and Science College, Thanjavur for giving the time to drawn this manuscript. 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Gene Rep. 27 , (2022) 101546. https://doi.org/10.1016/j.genrep.2022.101546 Nolkemper, S.; Reichling, J.; Stintzing, F.C.; Carle, R.; Schnitzler, P.: Antiviral effect of aqueous extracts from species of the Lamiaceae family against Herpes simplex virus type 1 and type 2 in vitro. Planta Med. Dec; 72 (15), 1378-82 (2006) doi: 10.1055/s-2006-951719. Noor, S.; Mohammad, T.; Rub, M.A.; Raza, A.; Azum, N.; Yadav, D.K.; Hassan, M.I.; Asiri, A.M.: Biomedical features and therapeutic potential of rosmarinic acid. Arch Pharm Res. Apr; 45 (4), 205-228 (2022) doi: 10.1007/s12272-022-01378-2. Prabhu, S.; Vijayakumar, S.; Manogar, P.; GaantyPragas, M.; Natanamurugaraj, G.: Homology modeling and molecular docking studies on Type II diabetes complica- tions reduced PPAR 𝛾receptor with various ligand molecules. Biomed. Pharmaco. 92 , 528-535 (2017) Srinivasan, Prabhu.; Subramaniyan, Vijayakumar.; Pabakaran, Praseetha.: Cyanobacterial metabolites as novel drug candidatesin corona viral therapies: A review. Chronic Dis Transl Med. 8 , 172–183 (2022) Swarup, V.; Ghosh, J.; Ghosh, S.; Saxena, A.; Basu, A.: Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis. Antimicrob Agents Chemother. Sep; 51 (9), 3367-70 (2007) doi: 10.1128/AAC.00041-07. Tsukamoto, Y.; Ikeda, S.; Uwai, K.; Taguchi, R.; Chayama, K.; Sakaguchi, T.; Narita, R.; Yao, W.; Takeuchi, F.; Otakaki, Y.; Watashi, K.; Wakita, T.; Kato, H.; Takashi Fujita.: Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction. PLoS ONE. 13 (5) (2018) e0197664, doi.org/10.1371/journal.pone.0197664 Vijayakumar, S.; Prabhu, S.; Rajalakhsmi, S.; Manogar, P.: Review on potential phytocompounds in drug development for Parkinson disease: a pharmacoinformatic approach. Inform Med Unlock. 5 , 15–25 (2016) https://doi.org/10.1016/j.imu.2016.09.00 Vijayakumar, S.; Sathiya, M.; Arulmozhi, P.; Prabhu, S.; Manogar, P.; Vinothkannan, R.; Parameswari, N.: Molecular docking and ADME properties of bioactive molecules against human acid-beta-glucosidase enzyme, cause of aucher’s disease. In Silico Pharmacol. 6 , 3 (2018) https://doi.org/10.1007/s40203-018-0039-3 Wahab, N.Z.A.; Ibrahim, N.; Kamarudin, M.K.A.; Lananan, F.; Juahir, H.; Ghazali, A.: In Vitro Antiviral Activity of Orthosiphon Stamineus Extract Against Dengue Virus Type 2. J Fundam Appl Sci. 10 (1S), 541-551 (2018) doi.org/10.4314/jfas.v10i1s.38 Wang, H.; Zhang, J.; Lu, Z.; Dai, W.; Ma, C.; Xiang, Y.: Identification of potential therapeutic targets and mechanisms of COVID-19 through network analysis and screening of chemicals and herbal ingredients. Brief. Bioinform. 00 (00), 1–15 (2021) doi.org/10.1093/bib/bbab373 Yi-Ching, Chung.; Feng-Chia, Hsieh.; Ying-Ju, Lin.; Tzong-Yuan, Wu.; Cheng-Wen, Lin.; Ching-Ting, Lin.; Nou-Ying, Tang.; Tzyy-Rong, Jinn.: Magnesium lithospermate B and rosmarinic acid, two compounds present in Salvia miltiorrhiza, have potent antiviral activity against enterovirus 71 infections. Euro. J. Pharmaco. 755 , 127–133 (2015) Tables Table. 1. Docking scores, binding energies and H bond interaction values of Rosmarinic acid with the docked viral proteins S. No. Ligand PDB ID Glide docking Score Energy values XP H-bond values 1. (R)-(+)-rosmarinic acid 1F5Q -10.847 -52.949 -4.376 2J7W -10.033 -48.078 -3.553 4OIG -7.259 -47.275 -3.223 Table. 2. Binding affinities among the residues of viral proteins and (R)-(+)-rosmarinic acid Docked complex Residues contribution for interactions Interactions Back bone with H-bond distances Other contacts 1F5Q with RA PHE146, GLU51 (Covalent binding), LYS33, PHE80, LEU83 & HIE84 PHE146 (2.14), GLU51 (1.47 & 2.06), LYS33 (1.70), , LEU83 (2.13) & HIE84 (2.14) PHE80 (π-π) 2J7W with RA THR571, VAL450, PHE354 & SER600 THR571 (2.28), VAL450 (2.10), PHE354 (1.71) & SER600 (2.54) - 4OIG with RA THR317 (Covalent binding), ARG257, LYS211, PHE277 & ASP278 THR317 (1.96 & 1.92), ARG257 (1.94), PHE277 (2.76) & ASP278 (1.92) LYS211 (Salt bridge & π-cation) and ARG257 (Salt bridge) Table. 3. The biomedical drug probabilities of (R)-(+)-rosmarinic acid by triggering or inhibiting the enzymes in human body (Predicted by Pass server) Biological activities Pa (probability to be active) Pi (probability to be inactive) Membrane integrity agonist 0.956 0.003 Feruloyl esterase inhibitor 0.938 0.003 Antihypoxic 0.921 0.002 Monophenol monooxygenase inhibitor 0.836 0.003 Antidiabetic 0.799 0.005 CYP2J substrate 0.804 0.020 GST A substrate 0.787 0.011 Reductant 0.779 0.004 Membrane permeability inhibitor 0.785 0.012 Pyruvate decarboxylase inhibitor 0.766 0.004 Preneoplastic conditions treatment 0.763 0.005 Chlordecone reductase inhibitor 0.780 0.024 Mucomembranous protector 0.779 0.024 Linoleate diol synthase inhibitor 0.757 0.008 APOA1 expression enhancer 0.751 0.004 Free radical scavenger 0.745 0.003 TNF expression inhibitor 0.744 0.005 4-Hydroxybenzoate 3-monooxygenase inhibitor 0.735 0.002 JAK2 expression inhibitor 0.745 0.013 MMP9 expression inhibitor 0.730 0.005 Anti-mutagenic 0.722 0.005 Lipid peroxidase inhibitor 0.719 0.005 Mucositis treatment 0.725 0.021 Ubiquinol-cytochrome-c reductase inhibitor 0.752 0.049 4-Coumarate-CoA ligase inhibitor 0.705 0.003 Gluconate 2-dehydrogenase (acceptor) inhibitor 0.710 0.051 Membrane integrity agonist 0.956 0.003 Feruloyl esterase inhibitor 0.938 0.003 Antihypoxic 0.921 0.002 Monophenol monooxygenase inhibitor 0.836 0.003 Antidiabetic 0.799 0.005 CYP2J substrate 0.804 0.020 Supplementary Files SupplementaryData.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2122165","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":141973268,"identity":"e0b50f07-c66e-4125-b0e4-7c4646a36405","order_by":0,"name":"A. 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The 2D template discloses the variety of interactions that exist between the hydroxy and oxygen groups of (R)-(+)-rosmarinic acid with 1F5Q.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/a45b2a49aa8c970e9502c657.jpeg"},{"id":27482011,"identity":"61f4ae9e-2e96-4577-9a4a-ea860199c79c","added_by":"auto","created_at":"2022-10-07 17:36:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1153206,"visible":true,"origin":"","legend":"\u003cp\u003eBinding Site of (R)-(+)-rosmarinic acid in 2J7W\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/0899fe436cdd9c66066b0d6b.png"},{"id":27482018,"identity":"630359b0-90d7-44b4-9289-1d4db080b32d","added_by":"auto","created_at":"2022-10-07 17:36:06","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":341871,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(R)-(+)-rosmarinic acid:\u003c/strong\u003e Residues and hydrogen bond contacts with their distance values among ligand and 2J7W b). The 2D template discloses the variety of interactions that exist between the hydroxy and oxygen groups of (R)-(+)-rosmarinic acid with 2J7W.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/d16ab08acdd482d8f8e68f47.jpeg"},{"id":27482911,"identity":"09bd0c81-7494-47fa-ad7c-12ee87a561a9","added_by":"auto","created_at":"2022-10-07 17:51:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":675040,"visible":true,"origin":"","legend":"\u003cp\u003eBinding Site of (R)-(+)-rosmarinic acid acid in 4OIG\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/bccc3c836281186cc9201184.png"},{"id":27482188,"identity":"2ae1873b-f539-4a8e-bfec-9ddf77b6a855","added_by":"auto","created_at":"2022-10-07 17:41:06","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":362063,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(R)-(+)-rosmarinic acid:\u003c/strong\u003e Residues and hydrogen bond contacts with their distance values among ligand and 4OIG b). The 2D template discloses the variety of interactions that exist between the hydroxy and oxygen groups of (R)-(+)-rosmarinic acid with 4OIG.\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/122b91c523b4aa251759d291.jpeg"},{"id":27482014,"identity":"fe8fb928-9aad-4978-ba4d-f672c4380782","added_by":"auto","created_at":"2022-10-07 17:36:06","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":129355,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePharmacophore hypothesis of (R)-(+)-rosmarinic acid: \u003c/strong\u003eA denotes hydrogen bond acceptor in pink color, D denotes hydrogen bond donor in blue) and R denotes aromatic rings in brown color from docked phytochemicals; A-D showed the active site of docked phytochemicals developed by 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9","display":"","copyAsset":false,"role":"figure","size":713939,"visible":true,"origin":"","legend":"\u003cp\u003eProbability scores reflect the most notable adverse effect of the Famiciclovir in the human health (Predicted by Pass Server)\u003c/p\u003e","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/dd9299835f6fa97cf509f411.jpeg"},{"id":27482694,"identity":"9dad5b34-cc98-42a2-9ffc-d51d1bfcca31","added_by":"auto","created_at":"2022-10-07 17:46:06","extension":"jpeg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":119912,"visible":true,"origin":"","legend":"\u003cp\u003eProbability scores reflect the most notable adverse effect of the Penciclovir in the human health (Predicted by Pass Server)\u003c/p\u003e","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/7f3927916cc09576dc8a00fc.jpeg"},{"id":27482189,"identity":"b7fd2fb9-ea93-4205-acf0-ef7ac0a3c897","added_by":"auto","created_at":"2022-10-07 17:41:06","extension":"jpeg","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":1003980,"visible":true,"origin":"","legend":"\u003cp\u003eProbability scores reflect the most notable adverse effect of the Valciclovir in the human health (Predicted by Pass Server)\u003c/p\u003e","description":"","filename":"floatimage11.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/117d0ec83f0f95f31dcf2009.jpeg"},{"id":27482022,"identity":"e073c74d-c5cb-4fb3-9b7d-9dbf1a1e0813","added_by":"auto","created_at":"2022-10-07 17:36:06","extension":"jpeg","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":1332688,"visible":true,"origin":"","legend":"\u003cp\u003eAcute toxicity of (R)-(+)-rosmarinic acid at different routes of administration of LD50 doses (Predicted by Gusar)\u003c/p\u003e","description":"","filename":"floatimage12.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/671434908db1b1cb803a54e5.jpeg"},{"id":27482987,"identity":"0c35c0d5-eb52-4cd8-b2dd-75ddd36c0faa","added_by":"auto","created_at":"2022-10-07 17:56:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4108147,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/a258cd54-0bc0-43a1-b685-47c11cd8f546.pdf"},{"id":27482013,"identity":"778d49b1-fe31-4634-96a6-fbfc5f94f75f","added_by":"auto","created_at":"2022-10-07 17:36:06","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":19664,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryData.docx","url":"https://assets-eu.researchsquare.com/files/rs-2122165/v1/f57bc44bc3b9dbd0806d7fb1.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003e\u003cstrong\u003eRosmarinic acid as a novel biomedical drug for inhibiting the replication of herpes and dengue viruses: An \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eIn-silico\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e assessment\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eViral infections have been a major cause of morbidity and mortality worldwide since the 20th century. In particular, viruses such as dengue, herpes virus, Ebola, AIDS, influenza and SARS are currently roaming the world as pandemics and epidemics (Ben-Shabat et al., 2019). Of concern is that human mortality from dengue and herpes virus infections is significantly increasing. The fact that the number of dengue cases reported to WHO has increased eight-fold over the past 20 years, from 505,430 cases in 2000 to over 2.4\u0026nbsp;million in 2010 and 5.2\u0026nbsp;million in 2019 supports this (WHO, 2022). On the other hand, worldwide 491\u0026nbsp;million people between the ages of 15 and 49 are reported to have HSV-2 infection, while 3.7\u0026nbsp;billion people under the age of 50 are reported to have HSV-1 infection (WHO, 2022).To fight the virus particles and inhibit their replication in the body, almost ninety types of antiviral drugs are available today, but one drug only control one virus. Similar to these drugs, the classic antiviral drugs such as interferon and ribavirin have antiviral potential against most viruses in \u003cem\u003ein-vitro\u003c/em\u003e studies, but often showed no effect in infected people during treatment (Ben-Shabat et al., 2019). Currently prescribed antiviral drugs are expensive, ineffective against some viruses and have harmful side effects on the human body with long-term use.\u003c/p\u003e \u003cp\u003eOn the other hand, natural substances, especially medicinal plants, have a broad therapeutic potential against a wide variety of infectious diseases caused by microorganisms such as viruses, fungi, bacteria, etc. In India, for example, two polyherbal formulation, Nilavembu Kudineer and Kabasura Kudineer, were have used to boost the immune system during the covid lockdown period. Although viruses pose a health burden to human race, most people currently rely heavily on medicinal plants to stimulate and modulate the immune system against the infectious complications of viruses (Prabhu et al., 2022). After consuming the plant extracts, the phytochemicals unfold their therapeutic potential either alone or in combination with other constituents as synergetic effects. In order to find such a multi-targeting viral drug molecule, the present study aimed to investigate the antiviral potential of (R)-(+)-rosmarinic acid .\u003c/p\u003e \u003cp\u003e(R)-(+)-rosmarinic acid (RA) is regarded as a promising phytochemical in the pharmaceutical industry due to its wide range of pharmacological effects (Chunxu et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). It is represented by the chemical formula C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e16\u003c/sub\u003eO\u003csub\u003e8\u003c/sub\u003e. It has been found that there are nearly 160 species of plants, including hornworts of bryophytes and angiosperms, both dicots and monocots (Huaquan et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). However, the RA was first discovered and isolated in 1958 in \u003cem\u003eRosmarinus officinalis\u003c/em\u003e L. Therefore, it is being considered as the main source of RA. Later, it was found in significant amounts in \u003cem\u003eThymus masticina, Ocimum tenuiflorum, Forsythia coriana\u003c/em\u003e, and \u003cem\u003eHyptis pectinate\u003c/em\u003e (Gordo et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Chunxu et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Because RA is water soluble, previous studies indicate that approximately 90% exhibits its therapeutic potential when even grinding and application with a universal solvent (Fecka, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). Consistent with this statement, this molecule is being studied for decades in \u003cem\u003ein-silico\u003c/em\u003e, \u003cem\u003ein-vitro\u003c/em\u003e and \u003cem\u003ein-vivo\u003c/em\u003e studies to screen its drug potential against health complications such as CNS diseases, diabetes, oncology and the diseases caused by microorganisms including dengue, herpes viruses, etc.\u003c/p\u003e \u003cp\u003eThere is currently no adequate treatment for viruses; whereas the drugs available are expensive and have side effects. Therefore, given the lack of antiviral drugs and the versatile pharmacological properties of (R)-(+)-rosmarinic acid, the present research aimed to investigate the antiviral potential of (R)-(+)-rosmarinic acid against dengue and herpes viruses. As it could possess effective antiviral potential to alleviate these viruses related problems.\u003c/p\u003e"},{"header":"2. Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Biological data\u003c/h2\u003e \u003cp\u003eInitially, (R)-(+)-rosmarinic acid was chosen as a ligand molecule and retrieved from the chemical database to find out its antiviral potential against the proteins of dengue and herpes viruses. Similar to the ligand, the viral proteins were retrieved from the protein database as in crystallographic form to dock with (R)-(+)-rosmarinic acid. The alphanumeric identities of the proteins were 1F5Q, 27JW and 4OIG (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.rcsb.com\" target=\"_blank\"\u003ewww.rcsb.com\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.rcsb.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Computational tools\u003c/h2\u003e \u003cp\u003eIn this research, the preparation of ligands and proteins was performed using the Maestro V.13.2 module tool. This software, consisting of LigPrep, Grid Generation, SiteMap and Glide XP, has each contributed significantly to the preparation of ligands and proteins. It ran on the highly configured Centox Linux operating system and was used for further investigation, in line with previous computer studies (Kalaimathi et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Prabhu et al., 2022).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Target preparation\u003c/h2\u003e \u003cp\u003eWith the Protein Preparation Wizard module, the proteins of dengue and herpes viruses were adjusted by removing the water molecules from them. In general, the water molecules-containing protein was not compatible for the molecular docking; therefore the water molecules were clean off from the proteins in order to allow for further investigation. Two gears such as preparation and refinement were utilized during this process to detect water molecules and remove them from the proteins, while the workspace analyzer was aided to add the missing residues in the proteins. Later, the proteins were shifted for docking using two more gears: optimization and minimization. The entire target preparation process has been completed in accordance with our previous studies (Christy Rani et al., 2022; Kalaimathi et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Active site prediction\u003c/h2\u003e \u003cp\u003eThis phase is critical in docking as it helps identify the correct putative binding pocket in the target molecules. Although the protein consists of an enormous number of binding sites, only one site could be used to generate a grid box. Therefore, it is chosen after its site volume and values were found to be higher than the other sites detected from this protein. Ultimately, only one site was chosen as a putative ligand binding pocket because of its potential binding metrics for ligand binding (Vijayakumar et al, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Grid generation\u003c/h2\u003e \u003cp\u003eThe binding site was stabilised as a good place for binding the (R)-(+)-rosmarinic acid by constructing the grid box with the gliding grid module. By constructing the lattice box using glide grid module, the putative binding site was stabilized as a suitable ligand site of (R)-(+)-rosmarinic acid. Prior to switching the molecular dopcking, the binding site was established to study the drug potential of (R)-(+)-rosmarinic acid by knowing the following parameters such as docking scores, binding affinities, etc. With this method, a grid box was constructed in order to dock the phytochemicals at the focal point of the protein within the targets. To fix the ligand binding site in the protein molecules, the grid box was constructed with X: 69.31, Y: 64.39 and Z: -14.86 for 1F5Q; whereas, the grid boxes to dengue viruses were constructed with X: 31.85, Y: 66.9 and Z: 30:43 for 2J7W and X: 38.95, Y: -20.17 and Z: -0.23 for 4UO5 respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Ligand preparation\u003c/h2\u003e \u003cp\u003eBefore docking with target molecules, the mole format of rosmarinic was prepared using the LigPrep (2.4) module. The Optimized Potentials for Liquid Simulations 2005 (OPLS2005) force field was also used to refine the topology of the detected ligand. Similar to protein preparation, two mechanisms such as tautomers and stereoisomers have been exploited in ligand preparation to reduce the geometric complexity of the ligand. The construction of the rosmarinic as 3D from 1D (smiles) and 2D was accomplished by the ligprep module. Later, the (R)-(+)-rosmarinic acid with a specific molecular weight or with a specific amount and type of functional groups with the appropriate chirality was properly processed and used for further research.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Molecular docking\u003c/h2\u003e \u003cp\u003eThe successfully prepared ligands and protein molecules were docked in the Xtra Precision Docking Mode. It was used to determine the strength of interactions between viral proteins and (R)-(+)-rosmarinic acid, specifically to know binding affinities and inhibition constants between them. To assess the effectiveness of (R)-(+)-rosmarinic acid as a treatment for these viral complications, docking metrics including docking scores, hydrophobic interactions, hydrogen bonding (side and back chains), pi-pi stacking, and salt bridge contacts were examined (Vijayakumar et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8. Pharmacophore analysis\u003c/h2\u003e \u003cp\u003eStructure-based and ligand-based techniques have been integrated into the energetic (e)-pharmacophore approach. The E-Pharmacophore scripting tool, developed to explore the pharmacophore hypothesis of rosmarnic acid. Using the Phase v 3.4 module, the pharmacophore sites of (R)-(+)-rosmarinic acid such as hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic group (H), positively ionizable (P), negatively ionizable (N), and aromatic ring (R) have been discovered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.9. Drug probability of Phytochemicals\u003c/h2\u003e \u003cp\u003eWith the help of the pass server, the drug potential of (R)-(+)-rosmarinic acid regard to the probabilities of active and inactive pharmacological properties were explored; whereas, the adverse effects the phytochemical and coneventional drugs were also careened. Using the Gusar, the acute toxicity of (R)-(+)-rosmarinic acid in rats was also noted at different doses of route of administration such as intravenous (IV), intraperitoneal (IP), subcutaneous (SC), and oral (O). (Kalaimathi et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cem\u003e3.1. Active sites of Viral Proteins\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTo locate the ligand binding region, the appropriate ligand site in the protein molecules was examined. Although the molecules possess numerous sites, the ligand binding sites were filtered based on their site score and volume. Here, this site analysis was revealed the residues consistency of three viral proteins such as 1F5Q, 2J7W and 4OIG. At the radius of 5A\u0026ordm;, the binding site residues of murine gamma herpesvirus cyclin complexed with human cyclin-dependent kinase 2 have been identified as LYS89, ASP86, GLN85, HIE84, LEU83, PHE82, GLU81, PHE80, LEU143, ALA144, ASP145, PHE146, GLY147, GLU51, LYS33, LEU32, ALA31, LEU134, GLN131, VAL64, ILE64 and LEU55. Similarly, \u0026nbsp;at the radius of 3A\u0026ordm;, the the binding site residues of NS5 RNA dependent RNA polymerase domain complexed with 3\u0026apos; dGTP have been identified as PRO319, THR317, PRO258, ASN207, ARG257, LYS211, ALA213, ASP276, PHE277 and ASP278. Furthermore, at the radius of 3A\u0026ordm;, the binding site residues of Flavivirus nonstructural protein 1 (NS1) molecule have been identified as ARG481, VAL450, THR571, LYS575, VAL577, VAL579, VAL358, LYS355, PHE354, TYR299, TRP302, ILE592, GLN602, SER600 and GLY599. Since all interactions with residues begin in this binding cavity, it plays key role in molecular docking exploration.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.2. Molecular docking\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the present \u003cem\u003einsilico\u003c/em\u003e apparoach, we examined the compatibility of (R)-(+)-rosmarinic acid \u0026nbsp;with the viral proteins of dengue and herpes viruses. Eventually, we found that the (R)-(+)-rosmarinic acid \u0026nbsp;was a possible drug because it contains better docking metrics for the docked dengue protein, including docking score, electrostatic energy, and hydrogen bonding. \u0026nbsp;Particularly, the docking scores revealed that it posses potential therapeutic effects to combat these viruses. It was additionally proven by the affinities between these molecules such as hydrongen bond, \u0026pi;-\u0026pi; stacking, electrostatic potential, \u0026pi;-cation, etc. It more clearly expresses the contribution and flexibility of the ligand with the docked viral proteins. Moreover, it has been clearly shown reveal as follows.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.2.1. (R)-(+)-rosmarinic acid \u0026nbsp;with Murine Gamma Herpesvirus Cyclin Complexed to Human Cyclin Dependent Kinase 2\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(R)-(+)-rosmarinic acid \u0026nbsp;was found to have a rather impressive docking score of -10.847 with this viral protein (Table 1). In order to examine its inhibitory constant and its binding affinities with murine gamma herpesvirus cyclin complexed with human cyclin-dependent kinase 2, the docked complex was examined (Fig. 1). At the end of the investigation, this research found that (R)-(+)-rosmarinic acid \u0026nbsp;has approximately six hydrogen contact lines with the herpesvirus amino acid residues. Amino acid residues such as PHE146, GLU51 (covalent bond), LYS33, PHE80, LEU83 and HIE84 were found to be in contact with (R)-(+)-rosmarinic acid \u0026nbsp;in significant levels of hydrogen bonding distances (Fig. 2a). GLU51 was known to have covalent bond interactions with (R)-(+)-rosmarinic acid ; the distances of these contacts were measured as 1.47 and 12.06. Moreover, the hydrogen bond contact distances of other residues with (R)-(+)-rosmarinic acid \u0026nbsp;were found as 2.14 in PHE146, 2.13 in LEU83, and 2.14 in HIE84; while the PHE80 was found as \u0026pi;-\u0026pi; stacking contacts (Fig. 2a and Table 2). Figure 2b shows which functional group is involved in hydrogen bonding contacts with (R)-(+)-rosmarinic acid . Except the residues PHE80 and LEU83, all the residues bind with the hydroxyl group (OH) of (R)-(+)-rosmarinic acid . LEU83, on the other hand, was found in contact with oxygen (O). However, PHE80 was found in contact with the main compound of (R)-(+)-rosmarinic acid , known as the pi-pi contact (green line) (Fig. 2b).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.2.2. (R)-(+)-rosmarinic acid \u0026nbsp;with\u003c/em\u003e NS5 RNA dependent RNA polymerase domain complexed with 3\u0026apos; dGTP\u003c/p\u003e\n\u003cp\u003e(R)-(+)-rosmarinic acid \u0026nbsp;was found to have a rather impressive docking score of -10.033 against this viral protein (Table 1). In order to examine its inhibitory constant and its binding affinities with NS5 RNA dependent RNA polymerase domain complexed with 3\u0026apos; dGTP, the docked complex was examined (Fig. 3). At the end of the investigation, this research found that (R)-(+)-rosmarinic acid has approximately four hydrogen contact lines with this viral protein amino acid residue. Amino acid residues such as THR571, VAL450, PHE354 and SER600 were found to be in contact with (R)-(+)-rosmarinic acid in significant levels of hydrogen bonding distances (Fig. 4a). The hydrogen bond contact distances of among these molecules were found as 2.28 in THR571, 2.10 in VAL450, 1.71 in PHE354 and 2.54 in SER600 (Fig. 4a and Table 2). Figure 4b shows which functional group is involved in hydrogen bonding contacts with (R)-(+)-rosmarinic acid. Except the residues SER600, all the residues bind with the hydroxyl group (OH) of (R)-(+)-rosmarinic acid. LEU83, on the other hand, was found in contact with oxygen (O). The contact lines have been shown quite accurately as binding affinities in Figure 2b.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.2.3. (R)-(+)-rosmarinic acid \u0026nbsp;with\u0026nbsp;\u003c/em\u003eFlavivirus nonstructural protein 1 (NS1)\u003c/p\u003e\n\u003cp\u003e(R)-(+)-rosmarinic acid \u0026nbsp;was found to have a rather impressive docking score of -7.259 against this viral protein (Table 1). In order to examine its inhibitory constant and its binding affinities with Flavivirus nonstructural protein 1 (NS1), the docked complex was examined (Fig. 5). At the end of the investigation, this research found that (R)-(+)-rosmarinic acid \u0026nbsp;has approximately five hydrogen contact lines with the herpesvirus amino acid residues. Amino acid residues such as THR317 (Covalent binding), ARG257, LYS211, PHE277 and ASP278 found to be in contact with (R)-(+)-rosmarinic acid \u0026nbsp;in significant levels of hydrogen bonding distances (Fig. 6a). THR317 was known to have covalent bond interactions with (R)-(+)-rosmarinic acid ; the distances of these contacts were measured as 1.96 and 1.92. Moreover, the hydrogen bonding contact distances of other residues with (R)-(+)-rosmarinic acid were found to be 2.76 in PHE277 and 1.92 in ASP278; while LYS211 and ARG257 were found as cation and salt bridge contacts, LYS211 in particular binds covalently with (R)-(+)-rosmarinic acid as a \u0026pi;-cation contact at one end and as a salt bridge contact at another end (Fig. 6a and Table 2). Figure 5b shows which functional group is involved in hydrogen bonding contacts with (R)-(+)-rosmarinic acid. Except the residues LYS211, all the residues bind with the hydroxyl group (OH) of (R)-(+)-rosmarinic acid (Fig. 6b).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMM-GBSA\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the \u003cem\u003eMM-GBSA\u0026nbsp;\u003c/em\u003evalidation, the free energy values of (R)-(+)-rosmarinic acid \u0026nbsp;are found to be -58.65 for 1F5Q, -52.17 for 277W and -48.52 for 4OIG (Table. 1). The final results of the investigation imply that (R)-(+)-rosmarinic acid \u0026nbsp;has the strong binding with the docked viral proteins.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.4.\u0026nbsp;Pharmacophore\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe data set was divided into active, moderately active and inactive regions by keeping the activity threshold in the 7.2 range. The (R)-(+)-rosmarinic acid \u0026nbsp;binding domain in terms of its five characteristics as shown in Figure 7 included the generic pharmacophore hypotheses due to its high survival value.\u003c/p\u003e\n\u003cp\u003e3.5. Drug probability active (Pa) and probability inactive (Pi) by Pass server\u003c/p\u003e\n\u003cp\u003eThe pass server\u0026apos;s prediction showed that (R)-(+)-rosmarinic acid is discovered to have broad pharmacological possibilities as notable Pa score, with a drug probability active score ranging from 0.710 to 0.956. Although (R)-(+)-rosmarinic acid showed broad pharmacological potential, only the most probable pharmacological activities were shown in Table 3. On the other hand, this prediction shows that the side effects of prescribed herpesvirus drugs such as aciclovir, famiciclovir, penciclovir and valaciclovir. Accordingly, the present research suggests that these drugs might lead to further complications for human health after administration as a treatment for the herpes virus (Supplementary Table 1-4). The most significant adverse effects of these drugs were shown in Figure 8-11.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.6. Rat acute toxicity of (R)-(+)-rosmarinic acid predicted by GUSAR\u003c/p\u003e\n\u003cp\u003eThe rate acute toxicity of (R)-(+)-rosmarinic acid was measured by LD50 at log10 (mmol/kg) and LD50 mg/kg levels. The applicability domain models were measured in terms of administration, including intraperitoneal administration (IP), intravenous administration (IV), oral administration (O), and subcutaneous administration (SC). The values of toxicity were clearly shown in Fig.2. \u0026nbsp;\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn the present computational research of antiviral drugs, (R)-(+)-rosmarinic acid was found to have remarkable antiviral abilities against the complications related to gamma herpes virus, NS5 RNA-dependent RNA polymerase domain complexed with 3'-dGTP and non-structural protein 1 (NS1) of flavivirus. The present research has recognized that (R)-(+)-rosmarinic acid is an effective antiviral drug for numerous viruses like dengue, herpes virus, etc. This statement was confirmed after evaluating the drug potential of this molecule in terms of binding affinities. Based on the present results, the existence of this molecule in plants and the antiviral potential of this molecule for other viruses have been clearly discussed as follows. Although the molecule was first discovered and isolated from \u003cem\u003eRosmarinus officinalis\u003c/em\u003e L, a recent review reported that (R)-(+)-rosmarinic acid has been widely isolated from many wild and cultivated plants worldwide over the past three decades. Consistent with this statement, plants such as \u003cem\u003eMelissa officinalis\u003c/em\u003e, \u003cem\u003eMentha balsamea\u003c/em\u003e Wild, \u003cem\u003eOriganum vulgare\u003c/em\u003e, \u003cem\u003eOrthosiphon stamineus\u003c/em\u003e, \u003cem\u003ePrunella vulgaris\u003c/em\u003e, \u003cem\u003eSalvia officinalis\u003c/em\u003e L, \u003cem\u003eRosmarinus officinalis\u003c/em\u003e L, \u003cem\u003eSalvia miltiorrhiza\u003c/em\u003e, \u003cem\u003eThymus vulgaris\u003c/em\u003e L and \u003cem\u003eZataria multiflora\u003c/em\u003e are reported to contain significant amounts of rosemary acid. The amounts of rosamarinic acid that scientists have isolated from various plants were listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. To assess the pharmacological potential of this phytochemical, it was tested on different targets in \u003cem\u003ein-silico\u003c/em\u003e, \u003cem\u003ein-vitro\u003c/em\u003e and \u003cem\u003ein-vivo\u003c/em\u003e models.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.1. Biomedical profiles and immune mechanisms of (R)-(+)-rosmarinic acid\u003c/h2\u003e \u003cp\u003eSince 1997 to date it has been reported to have various pharmacological properties as a novel candidate for inflammation, antioxidant potential, cancer, diabetic, antiviral potential for zoonotic and non-zoonotic diseases, neurodegenerative, hypertensive, antimicrobial and so on (Noor et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). On the other hand, it has also been used as folk medicine, cosmetics and dietary supplements since ancient times (Baba et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). In 2011, Hsu et al. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2011\u003c/span\u003e) found that (R)-(+)-rosmarinic acid markedly reduced IL-1 and TNF-α release, thereby ameliorating collagen-induced arthritis in \u003cem\u003ein-vivo\u003c/em\u003e conditions. These are part of the innate immune system of the human body. The cytokinins such as interferon-1 and TNF-α play a key role in activating the innate immune system. According to the research report of Hsu et al. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), we found that by inducing these two cytokinins, (R)-(+)-rosmarinic acid indirectly activates the innate immune system to protect the human body from harmful materials.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e4.2. Antiviral potential of (R)-(+)-rosmarinic acid\u003c/h2\u003e \u003cp\u003eThere are numerous studies demonstrating that (R)-(+)-(R)-(+)-rosmarinic acid has antiviral activity against a variety of viruses including Herpes simplex type 2 virus (Nolkemper et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2006\u003c/span\u003e), Japanese encephalitis virus (JEV) (Swarup et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), herpes simplex type 1 Virus (Ansari-Dogaheh et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2013\u003c/span\u003e), hepatitis B virus (Tsukamoto et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), Enterovirus 71 infection (Lin et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), dengue virus type 2 (Wahab et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), Severe acute coronavirus respiratory syndrome (SARS-CoV) (Wang et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), NS2B47-NS3 dengue virus (Mariya Jancy Rani et al., 2022) and so on. Following this statement, the few studies on the antiviral potential of (R)-(+)-rosmarinic acid are clearly discussed below to demonstrate its drug capability as a multiviral drug candidate.\u003c/p\u003e \u003cp\u003eIn 2006, a research by Nilkemper et al. (2006) tested the anti-herpes simplex virus on RC-37 cells in a plaque reduction assay using the extracts of \u003cem\u003eMelissa officinalis, Mentha piperita, Prunella Vulgaris\u003c/em\u003e and \u003cem\u003eRosmarinus vulgaris\u003c/em\u003e. In all tested extracts, (R)-(+)-rosmarinic acid was clearly identified as one of the most important phytochemicals. Finally, they stated that the extract may have strong antiviral activity against HSV-1 and HSV-2 due to the existence of (R)-(+)-rosmarinic acid in the extracts. On the other hand, a study by Swarup et al. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2007\u003c/span\u003e) reported that (R)-(+)-rosmarinic acid significantly reduced mortality in mice infected with Japanese encephalitis virus (JEV); there it significantly reduced viral loads (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and proinflammatory cytokine levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the mice than can be seen in the untreated mice at 8\u0026ndash;9 days post-infection.\u003c/p\u003e \u003cp\u003eA study by Ansari-Dogaheh et al. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) reported in 2013 that the (R)-(+)-rosmarinic acid was present in \u003cem\u003eZhumeria majdae\u003c/em\u003e at 1.3% at 50 g ml-1. It was confirmed by them after \u003cem\u003eZhumeria majdae\u003c/em\u003e extracts were treated on HSV-1. Eventually, they proposed that the extracts could be having anti-HSV 1 effect due to the existence of this phytochemical. In 2017, Chen et al. (2017) explored the antiviral potential of \u003cem\u003eMelissa officinalis\u003c/em\u003e extracts on EV71 after it was formulated with methanolic solvents. It showed the most remarkable anti-EV71 efficiency, plaque formation, cytopathic effect and viral protein synthesis in EV71-infected cells. They finally isolated (R)-(+)-rosmarinic acid as a biomedical active ingredient from this extract. They later proposed that it reduces viral attachment and entry cleavage of eukaryotic translation initiation factor 4G (eIF4G); generation of reactive oxygen species (ROS); and translocation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) from the nucleus to the cytoplasm. Similarly, at concentrations of 30\u0026micro;g/mL, the (R)-(+)-rosmarinic acid was reduced the EV71 IRES-mediated translation, while viral absorbance states for (R)-(+)-rosmarinic acid had an IC50 of 0.50 mM with a TI of 2.97, according to a Study by Chung et al. (2015). In addition, the 100 mg/mL of (R)-(+)-rosmarinic acid has reduced the formation of EV71 virus particles and VP1 protein, triggering the antiviral efficacy.\u003c/p\u003e \u003cp\u003eIn 2019, an \u003cem\u003ein-vitro\u003c/em\u003e study reported that (R)-(+)-rosmarinic acid possessed potent protective effects against human infection by EV71. Furthermore, it was found to not only protect cells from EV71-induced cytopathic effects, but also from EV71-induced pathogenesis and consequences. Therefore, they proposed that it has been significantly reduce EV71 infection in the early stages (Lin et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). A recent study by Mariya Jancy Rani et al. (2022) indicated that (R)-(+)-rosmarinic acid has a possible therapeutic effect for dengue following their \u003cem\u003ein-silico\u003c/em\u003e explorations. Eventually, they were suggested that (R)-(+)-rosmarinic acid could be a potent antiviral candidate for dengue than among the docked polyphenols of their research.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eViral infections have been one of the major causes of disease and death in human race worldwide. Dengue and herpes viruses in particular cause the worst health problems, sometimes leading to death. In this scenario, there is no adequate treatment to combat these viral particles and complications. Still, people around the world are trying to boost their immune systems by using plants, either alone or as polyherbal formulation, to fight off infectious agents, especially viruses. Therefore, the present research was also aimed to explore the antiviral potential from the pharmacologically versatile phytochemical (R)-(+)-rosmarinic acid. Current research shows that (R)-(+)-rosmarinic acid exhibits impressive hydrogen bonding interactions, strong docking values, and glide energy values. In addition, the pharmacokinetic property assessments have shown that this molecule possesses a variety of pharmacological properties by activating the enzymes of the human body. Accordingly, we believe that when tested in \u003cem\u003ein-vitro\u003c/em\u003e and \u003cem\u003ein-vivo\u003c/em\u003e experiments, (R)-(+)-rosmarinic acid would reveal drug activity against dengue and herpes virus replication. On the other hand, it has been found to have minimal side effects than the drugs currently prescribed for herpes viruses. Similarly, evaluation of the pharmacokinetic properties had shown that it has less toxicity to rats at doses of LD50 log10 (mmol/kg) and LD50 (mg/kg) by different routes of administration. Today's pharmaceutical sector is trying to discover a novel antiviral drug for many viruses; so far, however, no single drug is sufficient to combat the numerous viruses as a single drug. According to this investigation, we hope that the current research will show a clear way to find a drug that can effectively reduce the complications of various viruses.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChristy Rani:\u003c/strong\u003e Investigation, Formal Analysis, Original Draft Writing, Data Maintenance. \u003cstrong\u003eKalaimathi:\u003c/strong\u003e conceptualization, methodology, formal analysis, written review and editing. \u003cstrong\u003eJayashree:\u003c/strong\u003e investigation, formal analysis, validation. \u003cstrong\u003eMurugesan:\u003c/strong\u003e Investigation, Formal Analysis. \u003cstrong\u003ePrabhu:\u003c/strong\u003e conceptualization, methodology, review \u0026amp; editing and supervision. \u003cstrong\u003ePinkie Cherian:\u0026nbsp;\u003c/strong\u003eFormal analysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach author expresses his gratitude to their institutions for providing the opportunity to do develop this manuscript. The corresponding author expresses his thanks to the management of Annai Vailankanni Arts and Science College, Thanjavur for giving the time to drawn this manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003eAnsari-Dogaheh, M.; Sharififar, F.; Arabzadeh, A.M.; Shakibaic, M.; Heidarbeigi, M.: Inhibitory Effect of a Standard Extract of ZhumeriaMajdaeRech.F and Wendelbo. Against Herpes Simplex-1 Virus. J. Med. Sci. \u003cstrong\u003e13\u003c/strong\u003e (8), 755-760 (2013) DOI: 10.3923/jms.2013.755.760.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBaba, S.; Osakabe, N.; Natsume, M.; Terao, J.: Orally administered rosmarinic acid is present as the conjugated and/or methylated forms in plasma, and is degraded and metabolized to conjugated forms of cafeic acid, ferulic acid and m-coumaric acid. 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Pharmaco. \u003cstrong\u003e755\u003c/strong\u003e, 127\u0026ndash;133 (2015)\u003c/p\u003e"},{"header":"Tables","content":"\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eTable. 1.\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;Docking scores, binding energies and H bond interaction values of Rosmarinic acid with the docked viral proteins\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.3e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47.95pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 41.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eS. No.\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 41.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLigand\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 41.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-4.3pt;margin-bottom:0in;margin-left:-5.4pt;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 150%;font-family:\"Times New Roman\",serif;'\u003ePDB ID\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 41.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eGlide docking Score\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.7pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 41.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eEnergy values\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.95pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 41.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eXP H-bond values\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 47.95pt;border-color: currentcolor currentcolor windowtext;border-style: none none solid;border-width: medium medium 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e1.\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width:99.2pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(R)-(+)-rosmarinic acid\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;border: medium none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e1F5Q\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border: medium none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;color:black;'\u003e-10.847\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.7pt;border: medium none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-52.949\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.95pt;border: medium none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-4.376\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e2J7W\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.05pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-10.033\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-48.078\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-3.553\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:63.8pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.15pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e4OIG\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.05pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.15pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-7.259\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.15pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-47.275\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.15pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003e-3.223\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eTable. 2.\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;Binding affinities among the residues of viral proteins and\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(R)-(+)-rosmarinic acid\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 5.2e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 62.1pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 13.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 115%;font-family:\"Times New Roman\",serif;'\u003eDocked complex\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 155.95pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 13.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 115%;font-family:\"Times New Roman\",serif;'\u003eResidues contribution for interactions\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 297.65pt;border-color: windowtext currentcolor;border-style: solid none;border-width: 1pt medium;padding: 0in 5.4pt;height: 13.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 115%;font-family:\"Times New Roman\",serif;'\u003eInteractions\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.1pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eBack bone with\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eH-bond distances\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127.55pt;border-color: currentcolor currentcolor windowtext;border-style: none none solid;border-width: medium medium 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 17.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eOther contacts\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.1pt;border: medium none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='line-height:150%;font-family: \"Times New Roman\",serif;'\u003e1F5Q with RA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155.95pt;border: medium none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:-5.4pt;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003ePHE146, GLU51 (Covalent binding), LYS33, PHE80, LEU83 \u0026amp; HIE84\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border: medium none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:-5.4pt;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003ePHE146 (2.14), GLU51 (1.47 \u0026amp; 2.06), LYS33 (1.70), , LEU83 (2.13) \u0026amp; HIE84 (2.14)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127.55pt;border: medium none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003ePHE80 (\u0026pi;-\u0026pi;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.1pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='line-height:150%;font-family: \"Times New Roman\",serif;'\u003e2J7W \u0026nbsp;with RA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155.95pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:-5.4pt;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003eTHR571, VAL450, PHE354 \u0026amp; SER600\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:-5.4pt;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003eTHR571 (2.28), VAL450 (2.10), PHE354 (1.71) \u0026amp; SER600 (2.54)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127.55pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.1pt;border-color: currentcolor currentcolor windowtext;border-style: none none solid;border-width: medium medium 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='line-height:150%;font-family: \"Times New Roman\",serif;'\u003e4OIG with RA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155.95pt;border-color: currentcolor currentcolor windowtext;border-style: none none solid;border-width: medium medium 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:-5.4pt;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003eTHR317 (Covalent binding), ARG257, LYS211, PHE277 \u0026amp; ASP278\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-color: currentcolor currentcolor windowtext;border-style: none none solid;border-width: medium medium 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:-5.4pt;margin-bottom: 0in;margin-left:-5.4pt;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003eTHR317 (1.96 \u0026amp; 1.92), ARG257 (1.94), PHE277 (2.76) \u0026amp; ASP278 (1.92)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127.55pt;border-color: currentcolor currentcolor windowtext;border-style: none none solid;border-width: medium medium 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLYS211 (Salt bridge \u0026amp; \u0026pi;-cation) and ARG257 (Salt bridge)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eTable. 3.\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;The biomedical drug probabilities of (R)-(+)-rosmarinic acid by triggering or inhibiting the enzymes in human body (Predicted by Pass server)\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.7e+2pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eBiological activities\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003ePa (probability to be active)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003ePi (probability to be inactive)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMembrane integrity agonist\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.956\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.003\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eFeruloyl esterase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.938\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.003\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eAntihypoxic\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.921\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.002\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMonophenol monooxygenase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.836\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.003\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eAntidiabetic\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.799\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.005\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eCYP2J substrate\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.804\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.020\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eGST A substrate\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.787\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.011\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eReductant\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.779\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.004\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMembrane permeability inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.785\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.012\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003ePyruvate decarboxylase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.766\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.004\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003ePreneoplastic conditions treatment\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.763\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.005\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eChlordecone reductase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.780\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.024\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMucomembranous protector\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.779\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.024\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eLinoleate diol synthase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.757\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.008\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eAPOA1 expression enhancer\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.751\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.004\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eFree radical scavenger\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.745\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.003\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eTNF expression inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.744\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.005\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e4-Hydroxybenzoate 3-monooxygenase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.735\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.002\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eJAK2 expression inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.745\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.013\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMMP9 expression inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.730\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.005\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eAnti-mutagenic\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.722\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.005\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eLipid peroxidase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.719\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.005\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMucositis treatment\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.725\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.021\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:267.65pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eUbiquinol-cytochrome-c reductase inhibitor\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.752\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd 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Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rosmarinic acid, Anti-viral drug, Biomedical profile, Acute Toxicity","lastPublishedDoi":"10.21203/rs.3.rs-2122165/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2122165/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSince ancient times to till now, viruses such as dengue, herpes virus, ebola, AIDS, influenza, ebola, chicken meat and SARS have been roaming around causing great health burdens. To fight against these contagious viruses, people rely heavily on medicinal plants to enhance their immune system of innate and adaptive. In this research, the preparation of ligands and proteins was performed using the Maestro V.13.2 module tool. This software, consisting of LigPrep, Grid Generation, SiteMap and Glide XP, has each contributed significantly to the preparation of ligands and proteins. Ultimately, the research found that (R)-(+)-rosmarinic acid was found to have significant docking scores of -10.847 for herpes virus, of -10.033 for NS5 and \u0026minus;\u0026thinsp;7.259 for NS1. In addition, the Pass Server prediction indicates that rosmarinic acid possesses a diverse spectrum of enzymatic activities, as Probability Active (Pa) values ​​start at \u0026gt;\u0026thinsp;0.751; whereas it has fewer adverse effects than the drugs prescribed for viruses. Accordingly, it was found that the rate of acute toxicity values ​​of rosamric acid. According to this analysis, we expect that the current research will reveal a clear route to finding a medicine that can successfully lessen the complications of numerous viruses without causing any harmful effects. Ultimately, we concluded that (R)-(+)-rosmarinic acid would expose significant antiviral effects in \u003cem\u003ein-vitro\u003c/em\u003e and \u003cem\u003ein-vivo\u003c/em\u003e experiments and also this research would be a valuable asset for future especially those who wish to discover a drug molecule for variety of viruses.\u003c/p\u003e","manuscriptTitle":"Rosmarinic acid as a novel biomedical drug for inhibiting the replication of herpes and dengue viruses: An In-silico assessment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-07 17:36:04","doi":"10.21203/rs.3.rs-2122165/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"55f4881a-6a14-4ae7-a697-c30df27d1c29","owner":[],"postedDate":"October 7th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-10-07T17:36:04+00:00","versionOfRecord":[],"versionCreatedAt":"2022-10-07 17:36:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2122165","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2122165","identity":"rs-2122165","version":["v1"]},"buildId":"ApUGefWb6u5IBVtyqm6d5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}