key: cord-0910756-p12k2znh
authors: Wu, Yifei; Pegan, Scott D.; Crich, David; Desrochers, Ellison; Starling, Edward B.; Hansen, Madelyn C.; Booth, Carson; Nicole Mullininx, Lauren; Lou, Lei; Chang, Kuan Y.; Xie, Zhong-Ru
title: Polyphenols as Alternative Treatments of COVID-19
date: 2021-09-20
journal: Comput Struct Biotechnol J
DOI: 10.1016/j.csbj.2021.09.022
sha: 02eca5f443e0d89ac86700bce2c9092b17d176e5
doc_id: 910756
cord_uid: p12k2znh

Although scientists around the world have put lots of effort into the development of new treatments for COVID-19 since the outbreak, no drugs except Veklury (remdesivir) have been approved by FDA. There is an urgent need to discover some alternative antiviral treatment for COVID-19. Because polyphenols have been shown to possess antiviral activities, here we conducted a large-scale virtual screening for more than 400 polyphenols. Several lead compounds such as Petunidin 3-O-(6''-p-coumaroyl-glucoside) were identified to have promising binding affinities and convincing binding mechanisms. Analyzing the docking results and ADME properties sheds light on the potential efficacy of the top-ranked drug candidates and pinpoints the key residues on the target proteins for the future of drug development.

In March 2020, the World Health Organization declared a global pandemic of the novel coronavirus disease (COVID-19) [1] . This outbreak continues to wreak havoc around the world, causing over 640,000 deaths in the United States and over 4.5 million deaths worldwide by the end of August 2021 [2] . Thus, rapid discovery of small-molecule antiviral drugs that are therapeutic against COVID-19 continues to be a significant task [3] .

SARS-CoV-2, the viral agent responsible for COVID-19, is an enveloped, positive-sense, singlestranded RNA virus [4, 5] . Coronaviruses contain the largest-known RNA virus genomes, being roughly 26-32 kb and made up of at least six open reading frames (ORFs) encoding for proteins [5] . RNA viruses such as SARS-CoV-2 are replicated by releasing these RNA genomes into host cells, which in turn translate that RNA into proteins as if the viral RNA were the host cell's own RNA. The major ORF of SARS-CoV-2 encodes two overlapping polyproteins, PP1A and PP1B. These proteins are generated in the host cell and then cleaved into 16 non-structural proteins (NSP1-16) by two proteolytic enzymes: the main protease (M pro ) and papain-like protease (PL pro ) [6] . These NSPs then initiate replication and transcription of the viral genome by assembling the viral replicase complex on host cells membranes [3, 7, 8] . Thus, M pro and PL pro play vital roles in the replication of SARS-CoV-2 in the body; without them, the NSPs would not be released from the larger polyproteins, PP1A and PP1B.

The importance of these proteases to the viral life cycle has led researchers to wonder if they could be inactivated, and whether a protease inhibitor would be a useful treatment for COVID- 19 . Although coronaviruses cannot replicate if the proteolytic activity of PL pro or M pro is blocked [9] , no PL pro and M pro inhibitors used for COVID- 19 treatment have yet been approved. PL pro not only cleaves PP1A and PP1B at three distinct sites between NSP1-4, but also helps coronaviruses to elude the host's immune response through competitive interaction with ubiquitin and ISG15 [10] . Certain inhibitors of the PL pro from SARS-CoV, the virus responsible for the 2003 global outbreak of severe acute respiratory syndrome (SARS), also target the PL pro from SARS-CoV-2 and exhibit antiviral activity in monkey cells in vitro [10] . Furthermore, PL pro inhibition reduces the cytopathogenic effect and replication of SARS-CoV-2 while maintaining the interferon antiviral response in vitro [11] . On the other hand, M pro exclusively cleaves PP1A and PP1B at 11 distinct sites immediately following a glutamine residue [6] . Because no human host cell proteases have this substrate specificity, M pro is an ideal drug target [5, 12, 13] . A drug used to treat feline infectious peritonitis, a lethal coronavirus infection that affects cats, has been found to be capable of inhibiting the SARS-CoV-2 M pro and blocking viral replication [14] . Two protease inhibitors approved for treating hepatitis C virus have been demonstrated to inhibit the SARS-CoV-2 M pro and show strong antiviral activity in a mouse model [15] . Thus, further investigation into inhibitors of PL pro and M pro may very likely lead to the discovery of a safe, effective treatment for COVID-19.

Polyphenols are secondary plant metabolites with a plethora of health benefits, including strong antioxidant properties that defend against oxidative damage by free radicals and prevent chronic disease [16] . In light of the ongoing pandemic, researchers have investigated polyphenols' antiviral efficacy against COVID-19. Ghosh et al. found that the green tea polyphenols epigallocatechin gallate (EGCG), epicatechingallate, and gallocatechin-3-gallate interact strongly with one or both of the catalytic residues of the SARS-CoV-2 M pro [17] , and later demonstrated that six polyphenols from Broussonetia papyrifera inhibit the catalytic activity of M pro as well [18] . Khan et al. also found that EGCG interacted strongly with M pro [19] . Ansari et al. found that luteolin had a higher affinity for PL pro than the FDA-approved antiviral drug, remdesivir [20] . However, these studies were extremely limited in scope. There are around 500 unique polyphenol structures available for download on the Phenol-Explorer 3.6 database created by Neveu et al. [21] , and current studies investigating polyphenols as M pro and PL pro inhibitors are limited to a very small selection of molecules, mainly coming from green tea. Considering that promising results were found using such a small selection of polyphenols, it is possible that there are even better outcomes to be found within a larger sample.

Thus, to find potential therapeutic agents against COVID-19, this study screens a large number of polyphenols to bind to SARS-CoV-2 M pro or PL pro . The structures of 480 polyphenols were obtained from the aforementioned Phenol-Explorer 3.6 database, and molecular docking was conducted using Maestro. MM-GBSA scores were collected to quantify the affinity of the molecules for the proteins, and then ADME (Absorption, distribution, metabolism, and excretion) and drug-likeness properties were analyzed for further screening. (-87 .97 kcal/mol, -87.33 kcal/mol, and -85.70 kcal/mol, respectively). This study identifies multiple polyphenols with extremely high binding affinities to the SARS-CoV-2 M pro and PL pro as potential natural products used for COVID-19 treatment.

The 3D structures of 480 tested polyphenols were retrieved from Phenol-Explorer 3.6 (http://phenol-explorer.eu/). All the polyphenolic compounds were prepared using Ligprep in Maestro 12.4 (Schrödinger). The force field was OPLS3e by default [22] . The process of preparation includes adding hydrogens, computing correct partial charges, and generating possible conformations.

The protein structures of M pro (PDB ID: 7BRP) and PL pro (PDB ID: 6W9C) from RCSB's Protein Data Bank (https://www.rcsb.org/) [23] were prepared for use by Maestro in three steps: preprocessing, optimization, and minimization. The preprocessing included assigning bond orders, adding hydrogens, creating zero-order bonds to metals, creating disulfide, filling in missing side chains using Prime, deleting water molecules beyond 5.00 Å from het groups and generating het states using Epik [24] . PROPKA's default setting (pH=7.0) and the OPLS3e force field were applied in optimization and minimization.

To estimate the interactions between target proteins and polyphenols, we conducted ligand-protein docking by using the Ligand Docking panel in Maestro. Before running docking jobs, a receptor grid box was generated based on existing ligands in protein structures. For the structure of M pro (PDB ID: 7BRP), the existing ligand boceprevir was used to generate a receptor grid. In the structure of PL pro (PDB ID: 6W9C), the receptor grid was generated according to the same site on SARS-CoV PL pro (PDB ID: 3E9S). The size of the receptor grid box was set as default (20 Å). Ligand-protein docking was performed in extra-precision (XP) mode.

To predict the binding energies of polyphenols bound to M pro or PL pro , we performed Prime MM-GBSA (molecular mechanics generalized Born surface area) in Maestro. In the MM-GBSA panel, the pose viewer files of the docked complex were uploaded into the MM-GBSA panel. The force field was OPLS3e.

After binding energies calculation, we applied Qikprop module in Maestro to predict ADME and drug-likeness properties for further screening [25] . For Qikprop, the top-ranked polyphenols were prepared by using Ligprep. Finally, the descriptors such as RuleOfFive (RO5) and RuleOfThree (RO3) were applied to analyze the candidates.

AutoQSAR module of Schrodinger is a machine learning tool to build and apply quantitative structure-activity relationship (QSAR) models [26] . To build machine learning models, 61 M pro inhibitors and 20 PLpro inhibitors were retrieved from BindingDB [27] . The best model of each protease was used to predict half-maximal inhibitory concentration (IC 50 ) of the top-ranked polyphenols. The details of the polyphenols along with their predicted IC 50 values are presented in Table 1 and 3.

To further investigate the dynamic interactions between target proteins (M pro and PL pro ) and the top two polyphenols, we conducted Molecular dynamics (MD) simulations by using GROMACS version 2018.1 and CHARMM36 force field [28] . The starting coordinates of the protein-ligand complex were obtained from a ligand-protein docking study. Then, we used CHARMM-GUI to build the MD simulation solution boxes which were cubic boxes with length of 109 Å for 6W9C and 104 Å for 7BRP, and were filled with water [29] [30] [31] . Next, the minimized structures were equilibrated using an NVT ensemble (constant Number of particles, Volume, and Temperature) and NPT ensemble (the Number of particles, Pressure, and Temperature). The target equilibration temperature was 300 K. Finally, MD simulations were performed for 100 ns. After the MD simulations, we calculated the root-mean-square deviation (RMSD) and the energies.

To seek effective inhibitors from polyphenols against SARS-CoV-2 M pro , 480 polyphenols (ligand) were docked onto SARS-CoV-2 M pro (protein: PDB ID: 7BRP). Based on the docking poses, binding energies between the protein and ligand were calculated by MM-GBSA. Compared to three top drug candidates proposed by previous studies [17, 18] Table 1 , we find that the binding energy of Saquinavir is slightly better than that of Cyanidin 3-O-(6''-p-coumaroyl-glucoside) (-90.17 kcal/mol), however, the binding energies of Petunidin 3-O-(6''-p-coumaroyl-glucoside) and Malvidin 3,5-O-diglucosideare are better than those of the control group, which suggests the potential inhibitory effects of these polyphenols against SARS-CoV-2 M pro .

By comparing the 2D ligand-protein interactions of the top three polyphenols with M pro (Figure  1 ), we find that they all interact with Glu166 by forming hydrogen bonds: two hydrogen bonds for Petunidin 3-O-(6''-p-coumaroyl-glucoside), three for Malvidin 3,5-O-diglucoside, and one for cyanidin 3-O-(6''-p-coumaroyl-glucoside) ( Table 2 ). This result suggests that Glu166 is an essential residue in the binding pocket. According to the previous studies, Glu166 plays an important role in connecting the substrate binding site with the dimer interface [33] , and it also forms critical interactions with the residues of N-terminal finger on the heterologous monomer [33, 34] . In addition, the equivalent Glu169 on the M pro of MERS-CoV is also a key residue, which is crucial in both dimerization and catalysis [35] . [36] **The best-scored potential drug identified by a previous study [17] ***The best-scored potential drug identified by a previous study [18] **** The original ligand of 7BRP [37] a. QPlogS is predicted aqueous solubility. The recommended range is -6.5 ~ 0.5. b. RO5: number of violations of Lipinski's rule of five [38] . The recommended range: maximum is 4. c. RO3: Number of violations of Jorgensen's rule of three [39] . The recommended range: maximum is 3.

Furthermore, these top three polyphenols all interact with Thr26, Leu141, and Gln192 by forming hydrogen bonds. Petunidin 3-O-(6''-p-coumaroyl-glucoside) and Cyanidin 3-O-(6''-p-coumaroylglucoside) interact with Phe140 and Gly143 by forming hydrogen bonds. Petunidin 3-O-(6''-pcoumaroyl-glucoside) and Malvidin 3,5-O-diglucoside both interact with Asp187 by forming one hydrogen bond each. Additionally, His41 is also a critical residue which can interact with the top three polyphenols. Petunidin 3-O-(6''-p-coumaroyl-glucoside) interacts with His41 by forming two π-π stackings and one π-cation interaction, and Cyanidin 3-O-(6''-p-coumaroyl-glucoside) interacts with His41 via one π-cation interaction. The number of hydrogen bonds between the top three polyphenols and essential residues are listed in Table 1 . Accordingly, we propose that Petunidin 3-O-(6''-p-coumaroyl-glucoside), Malvidin 3,5-O-diglucoside, and Cyanidin 3-O-(6''-p-coumaroyl-glucoside) are the three best drug candidates among all 480 polyphenols tested against SARS-CoV-2 M pro .

To further screen the drug candidates for M pro , we calculated drug-likeness properties and predicted IC 50 on the top three polyphenols by using Qikprop and AutoQSAR, respectively. The results are shown in Table 1 . The polyphenols whose Qikprop descriptors (QPlogS, RuleOfFive, and RuleOfThree) fell out of the recommended range were excluded. For the results of AutoQSAR, it is interesting to note that the predicted IC 50 values of the top three polyphenols are all lower than 50 nM and Cyanidin 3-O-(6''-p-coumaroyl-glucoside) shows the best predicted IC 50 , which is generally consistent with the docking results. For the docking poses, S1/S2 subsites are being shown. The purple arrow indicates the hydrogen bond; the green line represents π-π stacking; the red line represents π -cation interaction.

To identify the best inhibitors of SARS-CoV-2 PL pro , we also docked 480 polyphenols on SARS-CoV-2 PL pro (PDB ID: 6W9C) by performing ligand-protein docking and MM-GBSA calculations (see Table 3 ) , the best-scored potential drug luteolin [20] , and a peptide inhibitor in the structure 6WX4 were selected as control.

From Table 3 , we find that the top three polyphenols show better binding energies than the control compounds, which indicates that these polyphenols might have stronger inhibitory effects.

From the 2D ligand-protein interactions in Figure 2 , we find that the top three compounds all can interact with Asp164 and Arg166 by forming hydrogen bonds. interacts with Gly266 and Tyr268 by forming one hydrogen bond, respectively. Notably, Gly266, Asn267, and Tyr268 are residues on blocking loop 2 (BL2), and BL2 plays an important role in inhibitor binding [40] . Hence, the interactions between the top two polyphenols and BL2 suggest strong inhibitory effects. Accordingly, we conclude that these two polyphenols can tightly bind onto the binding pocket. The number of hydrogen bonds between these three compounds and the essential residues are listed in Table 4 . 261.62 *a known prodrug of PL pro identified in our previous study [10] **the best-scored potential drug identified by the previous study [20] *** a peptide inhibitor in the structure of 6WX4 a. QPlogS is predicted aqueous solubility. The recommended range is -6.5 ~ 0.5. b. RO5: number of violations of Lipinski's rule of five [38] . The recommended range: maximum is 4. c. RO3: Number of violations of Jorgensen's rule of three [39] . The recommended range: maximum is 3.

The number of hydrogen bonds formed between the top three polyphenols and essential residues of SARS-CoV-2 PL pro . 1  2  1  Arg166  1  1  1  Glu167  1  1  Ser170  1  Pro248  1  Tyr264  1  Gly266  1  1  Asn267  1  Tyr268  1  Tyr273  1  1  Thr301  1 The pink arrow indicates the hydrogen bond; the green line represents π-π stacking; the red line represents π-cation interaction.

To further analyze the stability of complexes, we conducted MD simulation to calculate RMSD and energy for the top two candidates. First, RMSD can be used to assess the stability of a proteinligand complex. As shown in Figure 3A , the RMSD for the complex of 7BRP-Petunidin 3-O-(6''p-coumaroyl-glucoside) stabilized around 0.25 nm between 5 ns and 100 ns. In Figure 3B , Figure 4 . The energies of 7BRP complexes stabilized at around -1.13 × 10 6 KJ/mol. Interestingly ( Figure 4A and B), the energy of 6W9Ccomplexes stabilized at around -1.365 × 10 6 KJ/mol ( Figure 4C and D) . The RMSD and energy analysis show that the complexes of M pro or PL pro with their respective top two polyphenols stay stable during the simulation process. 

Many studies have shown natural products possessing antiviral properties against the Epstein-Barr virus [43, 44] , herpes simplex virus [45, 46] , influenza virus [47] , and other viruses targeting the respiratory tract [45, [48] [49] [50] . Since the 2003 outbreak of SARS, a number of natural products have been reported to inhibit the coronavirus which causes SARS (SARS-CoV) or its target proteins [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] . In addition, previous studies demonstrate that many polyphenols, including quercetin and its glycosylated derivatives, inhibit cell proliferation of tumor cells or microorganisms [67] [68] [69] [70] . Glycosylation of polyphenols could enhance water solubility, bioavailability, and their binding affinities to significant enzymes and improve the drug efficacy [71] [72] [73] . This result not only suggests that polyphenols are potential drug candidates, but also indicates that this study discovered more polyphenols for COVID-19 treatment. Based on the docking pose of each target protein, we find that the key residue(s) can interact with the best inhibitor candidate via multiple interactions. First, in the structure of M pro , Glu166 is a key residue for M pro dimerization and substrate binding pocket creation [74] . The best inhibitor candidate Petunidin 3-O-(6''-p-coumaroyl-glucoside) interacts with Glu166 side chain by forming two hydrogen bonds ( Figure 5A ), which makes an impact on increasing the binding energy. This result is consistent with the finding in our previous research which showed that saquinvir interacts with Glu166 [36] . Accordingly, Glu 166 is a key residue for M pro inhibitor discovery. In the structure of PL pro , the residues (Gly266-Gly271) in the BL2 loop are critical for inhibitor binding [7, 75] . From Figure 5B , we find that the best candidate of PL pro Kaempferol 3-O-sophoroside 7-O-glucoside forms hydrogen bonds with Gly266 and Asn267 which are the residues in the BL2 loop. Additionally, the second-best candidate Cyanidin 3-O-sambubioside 5-O-glucoside form one hydrogen bond with Tyr268 which is also an important residue in the BL2 loop. Therefore, more interactions between the inhibitor and the BL2 loop may increase the binding affinity.

In summary, this study demonstrates the potential of polyphenols being an alternative treatment of COVID-19. The docking results agree with previous studies identifying the key residues interacting with the binding inhibitors or prodrugs, but the proposed inhibitors in this study possess even better estimated binding affinities. However, most of the top-ranked polyphenols cannot be ordered for validation experiments currently. We are attempting to obtain some of them from other labs or produce them ourselves. The much better estimated binding affinities than previously identified compounds and rational binding mechanisms support their potential efficacy and provide the clues for the future drug development.

WHO Declares COVID-19 a Pandemic

An interactive web-based dashboard to track COVID-19 in real time

Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2

Coronavirus biology and replication: implications for SARS-CoV-2

The SARS-CoV-2 main protease as drug target

Severe Acute Respiratory Syndrome Coronavirus 2: From Gene Structure to Pathogenic Mechanisms and Potential Therapy

The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds

The Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus Has Deubiquitinating Activity

Coronavirus Protein Processing and RNA Synthesis Is Inhibited by the Cysteine Proteinase Inhibitor E64d

Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease

Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity

Targeting SARS-CoV-2 Main Protease: A Computational Drug Repurposing Study

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors. Science (80-)

Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

SARS-CoV-2 M pro inhibitors with antiviral activity in a transgenic mouse model . Science (80-)

Plant polyphenols as dietary antioxidants in human health and disease

Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (Mpro) inhibitors-an in silico docking and molecular dynamics simulation study

Identification of polyphenols from Broussonetia papyrifera as SARS CoV-2 main protease inhibitors using in silico docking and molecular dynamics simulation approaches

Identification of Dietary Molecules as Therapeutic Agents to Combat COVID-19 Using Molecular Docking Studies

Luteolin: A Dietary Molecule as Potential Anti-COVID-19 Agent

Phenol-Explorer: an online comprehensive database on polyphenol contents in foods

OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins

The Protein Data Bank

Epik: a software program for pK a prediction and protonation state generation for drug-like molecules

Schrödinger Release 2021-3: QikProp, Schrödinger, LLC

AutoQSAR: An automated machine learning tool for best-practice quantitative structure-activity relationship modeling

BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities

CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields

Simulations Using the CHARMM36 Additive Force Field

A web-based graphical user interface for CHARMM

CHARMM: The biomolecular simulation program

Cyanidin 3-Rutinoside and Cyanidin 3-Xylosylrutinoside as Primary Phenolic Antioxidants in Black Raspberry

Mutation of glu-166 blocks the substrate-induced dimerization of SARS coronavirus main protease

Mechanism of the maturation process of SARS-CoV 3CL protease

Critical assessment of the important residues involved in the dimerization and catalysis of MERS Coronavirus Main Protease

In silico identification of drug candidates against COVID-19

Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

Prediction of drug solubility from structure

Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV

Assessment of proton-coupled conformational dynamics of SARS and MERS coronavirus papain-like proteases: Implication for designing broad-spectrum antiviral inhibitors ARTICLES YOU MAY BE INTERESTED IN

Assessment of proton-coupled conformational dynamics of SARS and MERS coronavirus papain-like proteases: Implication for designing broad-spectrum antiviral inhibitors

Epstein Barr Virus lytic cycle in Burkitt's lymphoma cells by affecting multiple molecular targets

Resveratrol as a novel anti-herpes simplex virus nutraceutical agent: An overview. Viruses

Resveratrol suppresses nuclear factor-B in herpes simplex virus infected cells

Polygonum cuspidatum and its active components inhibit replication of the influenza virus through Toll-like receptor 9-induced interferon beta expression

Resveratrol-Mediated Gamma Interferon Reduction Prevents Airway Inflammation and Airway Hyperresponsiveness in Respiratory Syncytial Virus-Infected Immunocompromised Mice

Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection

Resveratrol inhibits rhinovirus replication and expression of inflammatory mediators in nasal epithelia

Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa

Medicinal herbal extracts of Sophorae radix, Acanthopanacis cortex, Sanguisorbae radix and Torilis fructus inhibit coronavirus replication in vitro

CoV 3C-like protease activity by theaflavin-3,3′-digallate (TF3). Evidence-based

Antiviral natural products and herbal medicines

Biflavonoids from Torreya nucifera displaying SARS-CoV 3CLpro inhibition

Antiviral effects of saikosaponins on human coronavirus 229E in vitro

Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds

Immunomodulatory and anti-SARS activities of Houttuynia cordata

Identification of natural compounds with antiviral activities against SARS-associated coronavirus

Dieckol, a SARS-CoV 3CLpro inhibitor, isolated from the edible brown algae Ecklonia cava

Synthesis and antiviral evaluation of 7-Oarylmethylquercetin derivatives against SARS-associated coronavirus (SCV) and hepatitis C virus (HCV)

Investigation of the pharmacophore space of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) NTPase/helicase by dihydroxychromone derivatives

Aryl diketoacids (ADK) selectively inhibit duplex DNA-unwinding activity of SARS coronavirus NTPase/helicase

Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction

Small Molecules Blocking the Entry of Severe Acute Respiratory Syndrome Coronavirus into Host Cells

Polyphenols enhance the activity of alkylating agents in leukaemia cell lines

Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells

Gram (−) microorganisms DNA polymerase inhibition, antibacterial and chemical properties of fruit and leaf extracts of Sorbus acuparia and Sorbus caucasica var. yaltirikii

Frangulosid as a novel hepatitis B virus DNA polymerase inhibitor: a virtual screening study

Elucidating the Inhibitory Effect of Resveratrol and Its Structural Analogs on Selected Nucleotide-Related Enzymes

Creating a Water-Soluble Resveratrol-Based Antioxidant by Site-Selective Enzymatic Glucosylation

The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man

Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies

A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication

In this research, YW, LL, and ZRX were supported by a start-up grant from the College of Engineering, University of Georgia and KYC was supported by Ministry of Science and Technology, R.O.C. under MOST-108-2221-E-019-052. We would like to acknowledgment Georgia Advanced Computing Resource Center (GACRC) and the College of Engineering's IT department of the UGA for technical support. This work used the Extreme Science and Engineering Discovery Environment (XSEDE) Bridges GPU at the Pittsburgh Supercomputing Center through allocation TGDPP180005.