Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach
Khushboo Singh, J J Patten, Andrea Dimet, Robert A Davey, Stanley J Watowich, Amit Chandra, Jesse Leverett
doi:10.21203/rs.3.rs-3888947/v1
The main protease (M Pro ) of SARS-CoV-2 plays a crucial role in viral replication and is a prime target for therapeutic interventions. Phytochemicals, known for their antiviral properties, have been previously identi ed as potential M Pro inhibitors in several in silico studies. However, the e cacy of these remains in question owing to the inherent exibility of the M Pro binding site, posing challenges in selecting suitable protein structures for virtual screening. In this study, we conducted an extensive analysis of the M Pro binding pocket, utilizing molecular dynamics (MD) simulations to explore its conformational diversity. Based on pocket volume and shape-based clustering, ve representative protein conformations were selected for virtual screening. Virtual screening of a library of ~ 48,000 phytochemicals suggested 39 phytochemicals as potential M Pro inhibitors. Based on subsequent MM-GBSA binding energy calculations and ADMET property predictions, ve compounds were advanced to cell-based viral replication inhibition assays, with three compounds (demethoxycurcumin, shikonin, and withaferin A) exhibiting signi cant (EC50 < 10 uM) inhibition of SARS-CoV-2 replication. Our study provides an understanding of the binding interactions between these phytochemicals and M Pro , contributing signi cantly to the identi cation of promising M Pro inhibitors. Furthermore, beyond its impact on therapeutic development against SARS-CoV-2, this research highlights a crucial role of proper nutrition in the ght against viral infections. Phytochemical Name Docking scores Conformation 1 Conformation 2 Conformation 3 Conformation 4 Conformation 5 1,3,6-Tri-O-Galloyl-Beta-D-Glucose -7.6 -8.8 -11.1 -7.5 -10.1 2'-Acetylacteoside -8.6 -9.5 -12.1 -13.4 -7.6 2''-O-Acetylrutin -10.3 -9.6 -12.2 -10.8 -10.4 *AHDPH -8.1 -9.0 -11.6 -7.5 -9.0 Balanophotannin E -7.5 -11.0 -12.9 -9.9 -8.4 **DDHHG -9.7 -8.3 -10.9 -11.3 -8.6 ***DHMMP-TRTH-TMMO-Chr-One -9.7 -10.5 -10.7 -9.1 -9.9 Eriodictyol 7-O-Sophoroside -12.6 -9.3 -10.0 -11.1 -10.0 Forsythiaside -10.3 -12.6 -14.3 -14.6 -9.2 Hyperin 6''-[glucosyl-(1->3)-rhamnoside] -9.7 -10.9 -15.9 -12.1 -11.9 Kaempferol 3-(3R-glucosylrutinoside) -10.0 -10.6 -12.0 -11.1 -8.5 Luteolin 7-rutinoside -9.8 -9.4 -14.4 -12.0 -9.9 Narcissin -9.7 -10.5 -10.7 -9.1 -9.9 Pectolinarin -8.9 -7.7 -13.9 -8.5 -7.5 Plantagineoside C -9.4 -10.3 -13.3 -10.4 -9.3 Quercetin 3-glucoside2''-gallate -7.8 -9.2 -12.1 -10.6 -7.5 Quercetin-3-o-rutinose -12.2 -11.0 -11.1 -11.5 -11.4 Salvianolic Acid L (SAL) -9.1 -8.2 -13.3 -11.3 -7.6 Shikonin -8.1 -8.4 -8.6 -8.9 -9.5 Shimobashiric Acid C (SAC) -8.2 -8.7 -10.5 -9.6 -10. 2 *AHDPH = (3R,5R)-3-Acetoxy-5-Hydroxy-1,7-Bis(3,4-Dihydroxyphenyl)Heptane. **DDHHG = (3R,5R)-3,5-Dihydroxy-1-(3,4-Dihydroxyphenyl)-7-(4-Hydroxyphenyl)-Heptane 3-O-Beta-D-Glucopyranoside.
For a comprehensive understanding of the model speci cations, validation, and performance, please refer to the AP11.0 user manual and relevant publications 74, 75 .
Cytoxicity Assay Vero cells were seeded using a multiDrop combi liquid dispenser (Thermo) into 384-well plates at a density of 500 cells/well suspended in 50 µL of media. Cells were allowed to recover and fully attach overnight (approximately 16 hours), at which point library compounds were dispensed into wells using an Echo 550 acoustic dispenser (Labcyte). A total of six nal concentrations where tested (50 µM, 25 µM, 12.5 µM, 6.25 µM, 3.125 µM, and 1.5625 µM) and wells were back lled with DMSO such that all wells contained a xed ratio of DMSO. Compounds were incubated with cells for 1 hour prior to addition of virus and then for an additional 24 hours, then xed with 10% formalin, permeabilized 0.1% Triton X-100, washed, and stained for SARS-CoV-2 N protein using a speci c antibody (Sino Biological # MM05) and uorescently labelled secondary antibody. Cells were counter stained with Hoechst 33342 to detect cell nuclei, washed, and imaged with a Cytation 1 (Biotek) automated. Each image was then analyzed with a custom work ow in Cell Pro ler (Broad Inst., Boston, MA) which involved counting of cell nuclei and infected cells. At least 4 replicates were used to construct dose response curves.
Statistics and data normalization The rate index is calculated from cell counts using the following formula: Where X c..
References
Abdusalam, Murugaiyah, Identi cation of Potential Inhibitors of 3CL Protease of SARS-CoV-2 From ZINC Database by Molecular Docking-Based Virtual Screening, Front. Mol. Biosci
Abraham, GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers, SoftwareX
Agrawal, Blunden, Phytochemicals Against SARS-COV-2 Infection, Nat. Prod. Commun
Alici, Tahtaci, Demir, Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19 -associated main enzymes, Comput. Biol. Chem
Anand, Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain, EMBO J
Anand, Ziebuhr, Wadhwani, Mesters, Hilgenfeld, Coronavirus main proteinase (3CLpro) structure: basis for the design of anti-SARS drugs, Science
Banks, Integrated modeling program applied chemical theory (IMPACT), J. Comp. Chem
Berendsen, Postma, Van Gunsteren, Dinola, Haak, Molecular dynamics with coupling to an external bath, J. Chem. Phys
Bharadwaj, Macrolactin A as a Novel Inhibitory Agent for SARS-CoV-2 M pro : Bioinformatics Approach, Appl. Biochem. Biotechnol
Biancatelli, Berrill, Catravas, Marik, Quercetin and vitamin C: an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19), Front. Immunol
Bzówka, Mitusińska, Raczyńska, Samol, Tuszyński et al., Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design, Int. J. Mol. Sci
Cappelli, Manganelli, Lombardo, Gissi, Benfenati, Validation of quantitative structure-activity relationship models to predict water-solubility of organic compounds, Sci. Total Environ
Chakraborty, The Natural Products Withaferin A and Withanone from the Medicinal Herb Withania somnifera Are Covalent Inhibitors of the SARS-CoV-2 Main Protease, J. Nat. Prod
Cherrak, Merzouk, Mokhtari-Soulimane, Potential bioactive glycosylated avonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies, PLoS One
Da Fonseca, Screening of Potential Inhibitors Targeting the Main Protease Structure of SARS-CoV-2 via Molecular Docking, and Approach with Molecular Dynamics, RMSD, RMSF, H-Bond, SASA and MMGBSA, Mol. Biotechnol,
doi:Preprintat10.1007/s12033-023-00831-xDai, Zhang, Jiang, Su, Li, Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease, Science
Darden, York, Pedersen, Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems, J. Chem. Phys
Dearden, In silico prediction of aqueous solubility, Expet Opin. Drug Discov
Dhawan, Anti-viral activity of Indian plants, Proc. Natl. Acad. Sci. India Sect. B Biol. Sci
Douangamath, Fearon, Gehrtz, Krojer, Lukacik, Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease, Nat. Commun
Durdagi, Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing, Structure
Durrant, POVME 2.0: An Enhanced Tool for Determining Pocket Shape and Volume Characteristics, J. Chem. Theory Comput
Estrada, Topological analysis of SARS CoV-2 main protease, Chaos
Fei, Contribution of traditional Chinese medicine combined with conventional western medicine treatment for the novel coronavirus disease (COVID-19), current evidence with systematic review and meta-analysis, Phytother. Res
Flynn, Comprehensive tness landscape of SARS-CoV-2 Mpro reveals insights into viral resistance mechanisms, Elife
Galan, Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-COV-2 infection, Pathog. Glob. Health
Ghosh, Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as a potential therapeutic lead against the main protease (Mpro) of SARS-CoV-2, J. Mol. Model
Gorbalenya, The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-ncov and naming it SARS-COV-2, Nature Microbiol
Gossen, A Blueprint for High A nity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics, ACS Pharmacol. Transl. Sci
Gupta, Identi cation of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies, J. Biomol. Struct. Dyn
Gupta, Structure-Based Virtual Screening and Biochemical Validation to Discover Potential Inhibitor of the SARS-CoV-2 Main Protease, ACS Omega
Henrich, Beutler, Matching the power of high throughput screening to the chemical diversity of natural products, Nat. Prod. Rep
Hess, Bekker, Berendsen, Fraaije, Lincs, A linear constraint solver for molecular simulations, J. Comp. Chem
Huang, Mackerell, CHARMM36 all-atom additive protein force eld: validation based on comparison to NMR data, J. Comput. Chem
Humphrey, Dalke, Schulten, VMD -Visual Molecular Dynamics, J. Mol. Graphics
Issa, The Main Protease of SARS-CoV-2 as a Target for Phytochemicals against Coronavirus, Plants
Jamhour, Phytochemicals As a Potential Inhibitor of COVID-19: An In-Silico Perspective, Russ. J. Phys. Chem
Jin, Structure of M pro from SARS-CoV-2 and discovery of its inhibitors, Nature
Jorgensen, Chandrasekhar, Madura, Impey, Klein, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys
Kaur, How do plants defend themselves against pathogens-Biochemical mechanisms and genetic interventions, Physiol. Mol. Biol. Plants
Khaerunnisa, Kurniawan, Awaluddin, Suhartati, Soetjipto, Potential Inhibitor of COVID-19 Main Protease (M pro ) From Several Medicinal Plant Compounds by Molecular Docking Study,
doi:10.20944/preprints202003.0226.v1Khanna, Herbal Immune-boosters: Substantial warriors of pandemiccovid-19 battle, Phytomedicine
Kneller, Kovalevsky, Coates, Structural plasticity of the SARS-COV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography, Nature Commun
Lachance, Charting, navigating, and populating natural product chemical space for drug discovery, J. Med. Chem
Lawson, Maccoss, Heer, Importance of rigidity in designing small molecule drugs to tackle protein-protein interactions (ppis) through stabilization of desired conformers, J. Med. Chem
Li, Abel, Zhu, Cao, Zhao et al., The VSGB 2.0 model: a next-generation energy model for high-resolution protein structure modeling, Proteins
Ling, Traditional Chinese medicine is a resource for drug discovery against 2019 novel coronavirus (SARS-COV-2), J. Integr. Med
Ma, Disul ram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspeci c Promiscuous SARS-CoV-2 Main Protease Inhibitors, ACS Pharmacol. Transl. Sci
Mani, Natural product-derived phytochemicals as potential agents against coronaviruses: a review, Virus Res
Mulu, The impact of curcumin-derived polyphenols on the structure and exibility COVID-19 main protease binding pocket: a molecular dynamics simulation study, PeerJ
Pettersen, UCSF Chimera -A visualization system for exploratory research and analysis, J. Comp. Chem
Remali, Aizat, A review on plant bioactive compounds and their modes of action against coronavirus infection, Front. Pharmacol
Ren, The newly emerged SARS-like coronavirus HCoV-EMC also has an "Achilles' heel": current effective inhibitor targeting a 3C-like protease, Protein Cell
Romano, Tatonetti, Informatics and computational methods in natural product drug discovery: A review and Perspectives, Front. Genet
Singh, Briggs, Impact of lymphoma-linked Asn11Tyr point mutation on the interaction between Bcl-2 and a BH3 mimetic: Insights from molecular dynamics simulation, Chem. Biol. Drug Design
Sztain, Amaro, Mccammon, Elucidation of cryptic and allosteric pockets within the SARS-CoV-2 protease, J. Chem. Inf. Model
Teli, Fragment-based design of SARS-CoV-2 Mpro inhibitors, Struct Chem
Vallejos, Ivermectin to prevent hospitalizations in patients with covid-19 (IVERCOR-covid19) a randomized, double-blind, placebocontrolled trial, BMC Infect. Dis
Wagner, POVME 3.0: Software for Mapping Binding Pocket Flexibility, J. Chem. Theory Comput
Wang, Structure of main protease from human coronavirus NL63: insights for wide spectrum anti-coronavirus drug design, Sci. Rep
Wu, A new coronavirus associated with human respiratory disease in China, Nature
Wu, Author Correction: A New Coronavirus Associated with Human Respiratory Disease in China, Nature
Xue, Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design, J. Virol
Yang, Screening of potential inhibitors targeting the main protease structure of SARS-CoV-2 via molecular docking, Front. Pharmacol
Yang, The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor, Proc. Natl. Acad. Sci
Zeng, CMAUP: A database of collective molecular activities of useful plants, Nucleic Acids Res
Zhang, Hilgenfeld, Crystal structure of SARS-CoV-2 Mpro in complex with the activity-based probe, biotin-PEG(4)-Abu-Tle-Leu-Glnvinylsulfone,
doi:10.2210/pdb6Z2E/pdbZhang, Structure-Based Discovery and Structural Basis of a Novel Broad-Spectrum Natural Product against the Main Protease of Coronavirus, J. Virol
Zhou, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature
{ 'institution': [{'name': 'Research Square'}],
'indexed': {'date-parts': [[2024, 1, 30]], 'date-time': '2024-01-30T00:22:24Z', 'timestamp': 1706574144551},
'posted': {'date-parts': [[2024, 1, 29]]},
'group-title': 'In Review',
'reference-count': 75,
'publisher': 'Research Square Platform LLC',
'license': [ { 'start': { 'date-parts': [[2024, 1, 29]],
'date-time': '2024-01-29T00:00:00Z',
'timestamp': 1706486400000},
'content-version': 'unspecified',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'accepted': {'date-parts': [[2024, 1, 22]]},
'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:p>The main protease (M<jats:sup>Pro</jats:sup>) of SARS-CoV-2 plays a crucial '
'role in viral replication and is a prime target for therapeutic interventions. '
'Phytochemicals, known for their antiviral properties, have been previously identified as '
'potential M<jats:sup>Pro</jats:sup> inhibitors in several in silico studies. However, the '
'efficacy of these remains in question owing to the inherent flexibility of the '
'M<jats:sup>Pro</jats:sup> binding site, posing challenges in selecting suitable protein '
'structures for virtual screening. In this study, we conducted an extensive analysis of the '
'M<jats:sup>Pro</jats:sup> binding pocket, utilizing molecular dynamics (MD) simulations to '
'explore its conformational diversity. Based on pocket volume and shape-based clustering, five '
'representative protein conformations were selected for virtual screening. Virtual screening '
'of a library of ~\u200948,000 phytochemicals suggested 39 phytochemicals as potential '
'M<jats:sup>Pro</jats:sup> inhibitors. Based on subsequent MM-GBSA binding energy calculations '
'and ADMET property predictions, five compounds were advanced to cell-based viral replication '
'inhibition assays, with three compounds (demethoxycurcumin, shikonin, and withaferin A) '
'exhibiting significant (EC50\u2009<\u200910 uM) inhibition of SARS-CoV-2 replication. Our '
'study provides an understanding of the binding interactions between these phytochemicals and '
'M<jats:sup>Pro</jats:sup>, contributing significantly to the identification of promising '
'M<jats:sup>Pro</jats:sup> inhibitors. Furthermore, beyond its impact on therapeutic '
'development against SARS-CoV-2, this research highlights a crucial role of proper nutrition '
'in the fight against viral infections.</jats:p>',
'DOI': '10.21203/rs.3.rs-3888947/v1',
'type': 'posted-content',
'created': {'date-parts': [[2024, 1, 29]], 'date-time': '2024-01-29T10:28:18Z', 'timestamp': 1706524098000},
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico '
'and cell-based approach',
'prefix': '10.21203',
'author': [ { 'given': 'Khushboo',
'family': 'Singh',
'sequence': 'first',
'affiliation': [{'name': 'Amway (United States)'}]},
{ 'given': 'J. J.',
'family': 'Patten',
'sequence': 'additional',
'affiliation': [{'name': 'Boston University'}]},
{ 'given': 'Andrea',
'family': 'Dimet',
'sequence': 'additional',
'affiliation': [{'name': 'The University of Texas Medical Branch at Galveston'}]},
{ 'given': 'Robert A.',
'family': 'Davey',
'sequence': 'additional',
'affiliation': [{'name': 'Boston University'}]},
{ 'given': 'Stanley J.',
'family': 'Watowich',
'sequence': 'additional',
'affiliation': [{'name': 'The University of Texas Medical Branch at Galveston'}]},
{ 'given': 'Amit',
'family': 'Chandra',
'sequence': 'additional',
'affiliation': [{'name': 'Amway (United States)'}]},
{ 'given': 'Jesse',
'family': 'Leverett',
'sequence': 'additional',
'affiliation': [{'name': 'Amway (United States)'}]}],
'member': '8761',
'reference': [ { 'key': 'ref1',
'doi-asserted-by': 'crossref',
'first-page': 'E7',
'DOI': '10.1038/s41586-020-2202-3',
'article-title': 'Author Correction: A New Coronavirus Associated with Human Respiratory '
'Disease in China',
'volume': '580',
'author': 'Wu F',
'year': '2020',
'unstructured': 'Wu, F., et al. Author Correction: A New Coronavirus Associated with '
'Human Respiratory Disease in China. Nature. 580, E7 (2020).',
'journal-title': 'Nature.'},
{ 'key': 'ref2',
'doi-asserted-by': 'crossref',
'first-page': '536',
'DOI': '10.1038/s41564-020-0695-z',
'article-title': 'The species severe acute respiratory syndrome-related coronavirus: '
'Classifying 2019-ncov and naming it SARS-COV-2',
'volume': '5',
'author': 'Gorbalenya AE',
'year': '2020',
'unstructured': 'Gorbalenya, A.E. et al. The species severe acute respiratory '
'syndrome-related coronavirus: Classifying 2019-ncov and naming it '
'SARS-COV-2. Nature Microbiol. 5, 536–544 (2020).',
'journal-title': 'Nature Microbiol'},
{ 'key': 'ref3',
'doi-asserted-by': 'crossref',
'first-page': '235',
'DOI': '10.1080/20477724.2021.1890887',
'article-title': 'Phase 2 randomized study on chloroquine, hydroxychloroquine or '
'ivermectin in hospitalized patients with severe manifestations of '
'SARS-COV-2 infection',
'volume': '115',
'author': 'Galan LE',
'year': '2021',
'unstructured': 'Galan, L.E. et al. Phase 2 randomized study on chloroquine, '
'hydroxychloroquine or ivermectin in hospitalized patients with severe '
'manifestations of SARS-COV-2 infection. Pathog. Glob. Health. 115, '
'235–242 (2021).',
'journal-title': 'Pathog. Glob. Health.'},
{ 'key': 'ref4',
'doi-asserted-by': 'crossref',
'first-page': '635',
'DOI': '10.1186/s12879-021-06348-5',
'article-title': 'Ivermectin to prevent hospitalizations in patients with covid-19 '
'(IVERCOR-covid19) a randomized, double-blind, placebo-controlled trial',
'volume': '21',
'author': 'Vallejos J',
'year': '2021',
'unstructured': 'Vallejos, J. et al. Ivermectin to prevent hospitalizations in patients '
'with covid-19 (IVERCOR-covid19) a randomized, double-blind, '
'placebo-controlled trial. BMC Infect. Dis. 21, 635 (2021)',
'journal-title': 'BMC Infect. Dis'},
{ 'key': 'ref5',
'author': 'Dhawan BN',
'year': '2012',
'unstructured': 'Dhawan, B.N. Anti-viral activity of Indian plants. Proc. Natl. Acad. '
'Sci. India Sect. B Biol. Sci. 82, 209–224 (2012).'},
{ 'key': 'ref6',
'first-page': '14',
'article-title': 'Phytochemical, antioxidant and microbial inhibitory effects of spondias '
'mombin leaf and stem bark extracts',
'volume': '9',
'year': '2014',
'unstructured': 'H.C.C, M. et al. Phytochemical, antioxidant and microbial inhibitory '
'effects of spondias mombin leaf and stem bark extracts. IOSR J. Pharm. '
'Biol. Sci. 9, pp. 14–17 (2014).',
'journal-title': 'IOSR J. Pharm. Biol. Sci.'},
{ 'key': 'ref7',
'doi-asserted-by': 'crossref',
'first-page': '153361',
'DOI': '10.1016/j.phymed.2020.153361',
'article-title': 'Herbal Immune-boosters: Substantial warriors of pandemiccovid-19 battle',
'volume': '85',
'author': 'Khanna K',
'year': '2021',
'unstructured': 'Khanna, K. et al. Herbal Immune-boosters: Substantial warriors of '
'pandemiccovid-19 battle. Phytomedicine. 85, 153361 (2021).',
'journal-title': 'Phytomedicine'},
{ 'key': 'ref8',
'doi-asserted-by': 'crossref',
'first-page': '8788',
'DOI': '10.1016/j.joim.2020.02.004',
'article-title': 'Traditional Chinese medicine is a resource for drug discovery against '
'2019 novel coronavirus (SARS-COV-2)',
'volume': '18',
'author': 'Ling C',
'year': '2020',
'unstructured': 'Ling, C. Traditional Chinese medicine is a resource for drug discovery '
'against 2019 novel coronavirus (SARS-COV-2). J. Integr. Med. 18, 8788 '
'(2020).',
'journal-title': 'J. Integr. Med.'},
{ 'key': 'ref9',
'doi-asserted-by': 'crossref',
'first-page': '589044',
'DOI': '10.3389/fphar.2020.589044',
'article-title': 'A review on plant bioactive compounds and their modes of action against '
'coronavirus infection',
'volume': '11',
'author': 'Remali J',
'year': '2021',
'unstructured': 'Remali, J. & Aizat, W.M. A review on plant bioactive compounds and their '
'modes of action against coronavirus infection. Front. Pharmacol. 11, '
'589044 (2021).',
'journal-title': 'Front. Pharmacol.'},
{ 'key': 'ref10',
'article-title': 'Contribution of traditional Chinese medicine combined with conventional '
'western medicine treatment for the novel coronavirus disease '
'(COVID-19), current evidence with systematic review and meta‐analysis',
'volume': '35',
'author': 'Fei J',
'year': '2021',
'unstructured': 'Fei, J. et al. Contribution of traditional Chinese medicine combined '
'with conventional western medicine treatment for the novel coronavirus '
'disease (COVID-19), current evidence with systematic review and '
'meta‐analysis. Phytother. Res. 35, (2021).',
'journal-title': 'Phytother. Res.'},
{ 'key': 'ref11',
'doi-asserted-by': 'crossref',
'first-page': '4283',
'DOI': '10.1021/acs.jmedchem.7b01120',
'article-title': 'Importance of rigidity in designing small molecule drugs to tackle '
'protein–protein interactions (ppis) through stabilization of desired '
'conformers',
'volume': '61',
'author': 'Lawson AD',
'year': '2017',
'unstructured': 'Lawson, A.D., MacCoss, M. & Heer, J.P. Importance of rigidity in '
'designing small molecule drugs to tackle protein–protein interactions '
'(ppis) through stabilization of desired conformers. J. Med. Chem. 61, '
'4283–4289 (2017).',
'journal-title': 'J. Med. Chem.'},
{ 'key': 'ref12',
'doi-asserted-by': 'crossref',
'first-page': '1284',
'DOI': '10.1039/c3np70052f',
'article-title': 'Matching the power of high throughput screening to the chemical '
'diversity of natural products',
'volume': '30',
'author': 'Henrich CJ',
'year': '2013',
'unstructured': 'Henrich, C.J. & Beutler, J.A. Matching the power of high throughput '
'screening to the chemical diversity of natural products. Nat. Prod. Rep. '
'30, 1284 (2013).',
'journal-title': 'Nat. Prod. Rep.'},
{ 'key': 'ref13',
'doi-asserted-by': 'crossref',
'first-page': '368',
'DOI': '10.3389/fgene.2019.00368',
'article-title': 'Informatics and computational methods in natural product drug '
'discovery: A review and Perspectives',
'volume': '10',
'author': 'Romano JD',
'year': '2019',
'unstructured': 'Romano, J.D. & Tatonetti, N.P. Informatics and computational methods in '
'natural product drug discovery: A review and Perspectives. Front. Genet. '
'10, 368 (2019).',
'journal-title': 'Front. Genet.'},
{ 'key': 'ref14',
'first-page': 'D1118-D1127',
'article-title': 'A database of collective molecular activities of useful plants',
'volume': 'CMAUP',
'author': 'Zeng X',
'year': '2018',
'unstructured': 'Zeng, X. et al. CMAUP: A database of collective molecular activities of '
'useful plants. Nucleic Acids Res. 47, D1118-D1127 (2018).',
'journal-title': 'Nucleic Acids Res'},
{ 'key': 'ref15',
'doi-asserted-by': 'crossref',
'first-page': '270',
'DOI': '10.1038/s41586-020-2012-7',
'article-title': 'A pneumonia outbreak associated with a new coronavirus of probable bat '
'origin',
'volume': '579',
'author': 'Zhou P',
'year': '2020',
'unstructured': 'Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus '
'of probable bat origin. Nature. 579, 270–273 (2020).',
'journal-title': 'Nature'},
{ 'key': 'ref16',
'doi-asserted-by': 'crossref',
'first-page': '265',
'DOI': '10.1038/s41586-020-2008-3',
'article-title': 'A new coronavirus associated with human respiratory disease in China',
'volume': '579',
'author': 'Wu F',
'year': '2020',
'unstructured': 'Wu, F. et al. A new coronavirus associated with human respiratory '
'disease in China. Nature. 579, 265–269 (2020).',
'journal-title': 'Nature.'},
{ 'key': 'ref17',
'doi-asserted-by': 'crossref',
'first-page': '3213',
'DOI': '10.1093/emboj/cdf327',
'article-title': 'Structure of coronavirus main proteinase reveals combination of a '
'chymotrypsin fold with an extra α-helical domain',
'volume': '21',
'author': 'Anand K',
'year': '2002',
'unstructured': 'Anand, K. et al. Structure of coronavirus main proteinase reveals '
'combination of a chymotrypsin fold with an extra α-helical domain. EMBO '
'J. 21, 3213–3224 (2002).',
'journal-title': 'EMBO J.'},
{ 'key': 'ref18',
'author': 'Yang H',
'year': '2003',
'unstructured': 'Yang, H. et al. The crystal structures of severe acute respiratory '
'syndrome virus main protease and its complex with an inhibitor. Proc. '
'Natl. Acad. Sci. 100, 13190–13195 (2003).'},
{ 'key': 'ref19',
'doi-asserted-by': 'crossref',
'first-page': '2515',
'DOI': '10.1128/JVI.02114-07',
'article-title': 'Structures of two coronavirus main proteases: implications for '
'substrate binding and antiviral drug design',
'volume': '82',
'author': 'Xue X',
'year': '2008',
'unstructured': 'Xue, X. et al. Structures of two coronavirus main proteases: '
'implications for substrate binding and antiviral drug design. J. Virol. '
'82, 2515–2527 (2008).',
'journal-title': 'J. Virol.'},
{ 'key': 'ref20',
'doi-asserted-by': 'crossref',
'first-page': '248',
'DOI': '10.1007/s13238-013-2841-3',
'article-title': 'The newly emerged SARS-like coronavirus HCoV-EMC also has an '
'"Achilles\' heel": current effective inhibitor targeting a 3C-like '
'protease',
'volume': '4',
'author': 'Ren Z',
'year': '2013',
'unstructured': 'Ren, Z. et al. The newly emerged SARS-like coronavirus HCoV-EMC also has '
'an "Achilles\' heel": current effective inhibitor targeting a 3C-like '
'protease. Protein Cell. 4, 248–250 (2013).',
'journal-title': 'Protein Cell.'},
{ 'key': 'ref21',
'doi-asserted-by': 'crossref',
'first-page': '22677',
'DOI': '10.1038/srep22677',
'article-title': 'Structure of main protease from human coronavirus NL63: insights for '
'wide spectrum anti-coronavirus drug design',
'volume': '6',
'author': 'Wang F',
'year': '2016',
'unstructured': 'Wang, F. et al. Structure of main protease from human coronavirus NL63: '
'insights for wide spectrum anti-coronavirus drug design. Sci. Rep. 6, '
'22677 (2016).',
'journal-title': 'Sci. Rep.'},
{ 'key': 'ref22',
'doi-asserted-by': 'crossref',
'first-page': '289',
'DOI': '10.1038/s41586-020-2223-y',
'article-title': 'Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors.',
'volume': '582',
'author': 'Jin Z',
'year': '2020',
'unstructured': 'Jin, Z. et al. Structure of Mpro from SARS-CoV-2 and discovery of its '
'inhibitors. Nature. 582, 289–293 (2020).',
'journal-title': 'Nature'},
{ 'key': 'ref23',
'doi-asserted-by': 'crossref',
'first-page': '3202',
'DOI': '10.1038/s41467-020-16954-7',
'article-title': 'Structural plasticity of the SARS-COV-2 3CL Mpro active site cavity '
'revealed by room temperature X-ray crystallography',
'volume': '11',
'author': 'Kneller DW',
'year': '2020',
'unstructured': 'Kneller, D.W., Kovalevsky, A. & Coates, L. Structural plasticity of the '
'SARS-COV-2 3CL Mpro active site cavity revealed by room temperature '
'X-ray crystallography. Nature Commun. 11, 3202 (2020).',
'journal-title': 'Nature Commun'},
{ 'key': 'ref24',
'doi-asserted-by': 'crossref',
'first-page': '3099',
'DOI': '10.3390/ijms21093099',
'article-title': 'Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro '
'Is a Challenging Target for Small-Molecule Inhibitor Design',
'volume': '21',
'author': 'Bzówka M',
'year': '2020',
'unstructured': 'Bzówka, M., Mitusińska, K., Raczyńska, A., Samol, A., Tuszyński, J.A., & '
'Góra, A. Structural and Evolutionary Analysis Indicate That the '
'SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor '
'Design. Int. J. Mol. Sci. 21, 3099 (2020).',
'journal-title': 'Int. J. Mol. Sci.'},
{ 'key': 'ref25',
'doi-asserted-by': 'crossref',
'first-page': '1079',
'DOI': '10.1021/acsptsci.0c00215',
'article-title': 'A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from '
'Activity-Based Compound Library Screening Guided by Analysis of Protein '
'Dynamics',
'volume': '4',
'author': 'Gossen J',
'year': '2021',
'unstructured': 'Gossen, J. et al. A Blueprint for High Affinity SARS-CoV-2 Mpro '
'Inhibitors from Activity-Based Compound Library Screening Guided by '
'Analysis of Protein Dynamics. ACS Pharmacol. Transl. Sci. 4, 1079–1095 '
'(2021).',
'journal-title': 'ACS Pharmacol. Transl. Sci.'},
{ 'key': 'ref26',
'doi-asserted-by': 'crossref',
'first-page': 'e77433',
'DOI': '10.7554/eLife.77433',
'article-title': 'Comprehensive fitness landscape of SARS-CoV-2 Mpro reveals insights '
'into viral resistance mechanisms',
'volume': '11',
'author': 'Flynn JM',
'year': '2022',
'unstructured': 'Flynn, J.M. et al. Comprehensive fitness landscape of SARS-CoV-2 Mpro '
'reveals insights into viral resistance mechanisms. Elife. 11, e77433 '
'(2022).',
'journal-title': 'Elife.'},
{ 'key': 'ref27',
'doi-asserted-by': 'crossref',
'first-page': '061102',
'DOI': '10.1063/5.0013029',
'article-title': 'Topological analysis of SARS CoV-2 main protease',
'volume': '30',
'author': 'Estrada E',
'year': '2020',
'unstructured': 'Estrada, E. Topological analysis of SARS CoV-2 main protease. Chaos. 30, '
'061102 (2020).',
'journal-title': 'Chaos'},
{ 'key': 'ref28',
'doi-asserted-by': 'crossref',
'first-page': '3371',
'DOI': '10.1007/s12010-021-03608-7',
'article-title': 'Macrolactin A as a Novel Inhibitory Agent for SARS-CoV-2 Mpro: '
'Bioinformatics Approach',
'volume': '193',
'author': 'Bharadwaj KK',
'year': '2021',
'unstructured': 'Bharadwaj, K.K. et al. Macrolactin A as a Novel Inhibitory Agent for '
'SARS-CoV-2 Mpro: Bioinformatics Approach. Appl. Biochem. Biotechnol. '
'193, 3371–3394 (2021).',
'journal-title': 'Appl. Biochem. Biotechnol.'},
{ 'key': 'ref29',
'doi-asserted-by': 'crossref',
'first-page': '603037',
'DOI': '10.3389/fmolb.2020.603037',
'article-title': 'Identification of Potential Inhibitors of 3CL Protease of SARS-CoV-2 '
'From ZINC Database by Molecular Docking-Based Virtual Screening',
'volume': '7',
'author': 'Abdusalam AAA',
'year': '2020',
'unstructured': 'Abdusalam, A.A.A., & Murugaiyah, V. Identification of Potential '
'Inhibitors of 3CL Protease of SARS-CoV-2 From ZINC Database by Molecular '
'Docking-Based Virtual Screening. Front. Mol. Biosci. 7, 603037 (2020).',
'journal-title': 'Front. Mol. Biosci.'},
{ 'key': 'ref30',
'doi-asserted-by': 'crossref',
'first-page': '33151',
'DOI': '10.1021/acsomega.0c04808',
'article-title': 'Structure-Based Virtual Screening and Biochemical Validation to '
'Discover a Potential Inhibitor of the SARS-CoV-2 Main Protease',
'volume': '5',
'author': 'Gupta A',
'year': '2020',
'unstructured': 'Gupta, A. et al. Structure-Based Virtual Screening and Biochemical '
'Validation to Discover a Potential Inhibitor of the SARS-CoV-2 Main '
'Protease. ACS Omega. 5, 33151–33161 (2020).',
'journal-title': 'ACS Omega'},
{ 'key': 'ref31',
'doi-asserted-by': 'crossref',
'first-page': '5047',
'DOI': '10.1021/ct500381c',
'article-title': 'POVME 2.0: An Enhanced Tool for Determining Pocket Shape and Volume '
'Characteristics',
'volume': '10',
'author': 'Durrant JD',
'year': '2014',
'unstructured': 'Durrant, J.D. et al. POVME 2.0: An Enhanced Tool for Determining Pocket '
'Shape and Volume Characteristics. J. Chem. Theory Comput. 10, 5047–5056 '
'(2014).',
'journal-title': 'J. Chem. Theory Comput'},
{ 'key': 'ref32',
'doi-asserted-by': 'crossref',
'first-page': '4584',
'DOI': '10.1021/acs.jctc.7b00500',
'article-title': 'POVME 3.0: Software for Mapping Binding Pocket Flexibility',
'volume': '13',
'author': 'Wagner JR',
'year': '2017',
'unstructured': 'Wagner, J.R. et al. POVME 3.0: Software for Mapping Binding Pocket '
'Flexibility. J. Chem. Theory Comput. 13, 4584–4592 (2017).',
'journal-title': 'J. Chem. Theory Comput.'},
{ 'key': 'ref33',
'doi-asserted-by': 'crossref',
'first-page': '1382',
'DOI': '10.1016/j.str.2021.07.007',
'article-title': 'Near-physiological-temperature serial crystallography reveals '
'conformations of SARS-CoV-2 main protease active site for improved drug '
'repurposing',
'volume': '29',
'author': 'Durdagi S',
'year': '2021',
'unstructured': 'Durdagi, S. et al. Near-physiological-temperature serial crystallography '
'reveals conformations of SARS-CoV-2 main protease active site for '
'improved drug repurposing. Structure. 29, 1382–1396 (2021).',
'journal-title': 'Structure.'},
{ 'key': 'ref34',
'doi-asserted-by': 'crossref',
'first-page': '3495',
'DOI': '10.1021/acs.jcim.1c00140',
'article-title': 'Elucidation of cryptic and allosteric pockets within the SARS-CoV-2 '
'protease',
'volume': '61',
'author': 'Sztain T',
'year': '2021',
'unstructured': 'Sztain, T., Amaro, R., & McCammon, J.A. Elucidation of cryptic and '
'allosteric pockets within the SARS-CoV-2 protease. J. Chem. Inf. Model. '
'61, 3495–3501 (2021).',
'journal-title': 'J. Chem. Inf. Model'},
{ 'key': 'ref35',
'doi-asserted-by': 'crossref',
'first-page': '962863',
'DOI': '10.3389/fphar.2022.962863',
'article-title': 'Screening of potential inhibitors targeting the main protease structure '
'of SARS-CoV-2 via molecular docking',
'volume': '13',
'author': 'Yang X',
'year': '2022',
'unstructured': 'Yang, X. et al. Screening of potential inhibitors targeting the main '
'protease structure of SARS-CoV-2 via molecular docking. Front. '
'Pharmacol. 13, 962863 (2022).',
'journal-title': 'Front. Pharmacol.'},
{ 'key': 'ref36',
'doi-asserted-by': 'publisher',
'author': 'Fonseca AM',
'year': '2023',
'unstructured': 'da Fonseca, A.M. et al. Screening of Potential Inhibitors Targeting the '
'Main Protease Structure of SARS-CoV-2 via Molecular Docking, and '
'Approach with Molecular Dynamics, RMSD, RMSF, H-Bond, SASA and MMGBSA. '
'Mol. Biotechnol. Preprint at 10.1007/s12033-023-00831-x (2023).',
'DOI': '10.1007/s12033-023-00831-x'},
{ 'key': 'ref37',
'doi-asserted-by': 'crossref',
'first-page': '2155',
'DOI': '10.1007/s11224-022-02031-w',
'article-title': 'Fragment-based design of SARS-CoV-2 Mpro inhibitors',
'volume': '33',
'author': 'Teli DM',
'year': '2022',
'unstructured': 'Teli, D.M. et al. Fragment-based design of SARS-CoV-2 Mpro inhibitors. '
'Struct Chem. 33, 2155–2168 (2022).',
'journal-title': 'Struct Chem'},
{ 'key': 'ref38',
'doi-asserted-by': 'crossref',
'first-page': '1589',
'DOI': '10.1134/S0036024422070251',
'article-title': 'Phytochemicals As a Potential Inhibitor of COVID-19: An In-Silico '
'Perspective',
'volume': '96',
'author': 'Jamhour RMAQ',
'year': '2022',
'unstructured': 'Jamhour, R.M.A.Q. et al. Phytochemicals As a Potential Inhibitor of '
'COVID-19: An In-Silico Perspective. Russ. J. Phys. Chem. 96, 1589–97 '
'(2022).',
'journal-title': 'Russ. J. Phys. Chem.'},
{ 'key': 'ref39',
'article-title': 'Phytochemicals Against SARS-COV-2 Infection',
'volume': '18',
'author': 'Agrawal PK',
'year': '2023',
'unstructured': 'Agrawal, P.K., & Blunden, G. Phytochemicals Against SARS-COV-2 '
'Infection. Nat. Prod. Commun. 18, (2023).',
'journal-title': 'Nat. Prod. Commun.'},
{ 'key': 'ref40',
'doi-asserted-by': 'crossref',
'first-page': '1451',
'DOI': '10.3389/fimmu.2020.01451',
'article-title': 'Quercetin and vitamin C: an experimental, synergistic therapy for the '
'prevention and treatment of SARS-CoV-2 related disease (COVID-19)',
'volume': '11',
'author': 'Biancatelli RMLC',
'year': '2020',
'unstructured': 'Biancatelli, R.M.L.C., Berrill, M., Catravas, J., & Marik, P.E. '
'Quercetin and vitamin C: an experimental, synergistic therapy for the '
'prevention and treatment of SARS-CoV-2 related disease (COVID-19). '
'Front. Immunol. 11, 1451 (2020).',
'journal-title': 'Front. Immunol.'},
{ 'key': 'ref41',
'doi-asserted-by': 'crossref',
'first-page': '197989',
'DOI': '10.1016/j.virusres.2020.197989',
'article-title': 'Natural product-derived phytochemicals as potential agents against '
'coronaviruses: a review',
'volume': '284',
'author': 'Mani JS',
'year': '2020',
'unstructured': 'Mani J.S et al. Natural product-derived phytochemicals as potential '
'agents against coronaviruses: a review. Virus Res. 284, 197989. (2020).',
'journal-title': 'Virus Res.'},
{ 'key': 'ref42',
'doi-asserted-by': 'crossref',
'first-page': '1862',
'DOI': '10.3390/plants11141862',
'article-title': 'The Main Protease of SARS-CoV-2 as a Target for Phytochemicals against '
'Coronavirus',
'volume': '11',
'author': 'Issa SS',
'year': '2022',
'unstructured': 'Issa S.S. et al. The Main Protease of SARS-CoV-2 as a Target for '
'Phytochemicals against Coronavirus. Plants. 11, 1862 (2022).',
'journal-title': 'Plants'},
{'key': 'ref43', 'unstructured': 'AP11.0, SimulationsPlus LLC, Lancaster, CA.'},
{ 'key': 'ref44',
'doi-asserted-by': 'crossref',
'DOI': '10.1016/j.compbiolchem.2022.107657',
'article-title': 'Design and various in silico studies of the novel curcumin derivatives '
'as potential candidates against COVID-19 -associated main enzymes',
'author': 'Alici H',
'year': '2022',
'unstructured': 'Alici, H., Tahtaci, H., & Demir, K. Design and various in silico studies '
'of the novel curcumin derivatives as potential candidates against '
'COVID-19 -associated main enzymes. Comput. Biol. Chem. (2022).',
'journal-title': 'Comput. Biol. Chem.'},
{ 'key': 'ref45',
'doi-asserted-by': 'crossref',
'first-page': 'e11590',
'DOI': '10.7717/peerj.11590',
'article-title': 'The impact of curcumin-derived polyphenols on the structure and '
'flexibility COVID-19 main protease binding pocket: a molecular dynamics '
'simulation study',
'volume': '9',
'author': 'Mulu A',
'year': '2021',
'unstructured': 'Mulu, A. et al. The impact of curcumin-derived polyphenols on the '
'structure and flexibility COVID-19 main protease binding pocket: a '
'molecular dynamics simulation study. PeerJ. 9, e11590 (2021).',
'journal-title': 'PeerJ'},
{ 'key': 'ref46',
'doi-asserted-by': 'publisher',
'author': 'Khaerunnisa S',
'year': '2020',
'unstructured': 'Khaerunnisa, S., Kurniawan, H., Awaluddin, R., Suhartati, S., & '
'Soetjipto, S. Potential Inhibitor of COVID-19 Main Protease (Mpro) From '
'Several Medicinal Plant Compounds by Molecular Docking Study. Preprint '
'at https://doi.org/10.20944/preprints202003.0226.v1 (2020).',
'DOI': '10.20944/preprints202003.0226.v1'},
{ 'key': 'ref47',
'doi-asserted-by': 'crossref',
'first-page': '97',
'DOI': '10.1007/s00894-021-04703-6',
'article-title': 'Structure-activity relationship (SAR) and molecular dynamics study of '
'withaferin-A fragment derivatives as a potential therapeutic lead '
'against the main protease (Mpro) of SARS-CoV-2',
'volume': '27',
'author': 'Ghosh A',
'year': '2021',
'unstructured': 'Ghosh, A. et al. Structure-activity relationship (SAR) and molecular '
'dynamics study of withaferin-A fragment derivatives as a potential '
'therapeutic lead against the main protease (Mpro) of SARS-CoV-2. J. Mol. '
'Model. 27, 97 (2021).',
'journal-title': 'J. Mol. Model.'},
{ 'key': 'ref48',
'doi-asserted-by': 'crossref',
'first-page': '2340',
'DOI': '10.1021/acs.jnatprod.2c00521',
'article-title': 'The Natural Products Withaferin A and Withanone from the Medicinal Herb '
'Withania somnifera Are Covalent Inhibitors of the SARS-CoV-2 Main '
'Protease',
'volume': '85',
'author': 'Chakraborty S',
'year': '2022',
'unstructured': 'Chakraborty, S. et al. The Natural Products Withaferin A and Withanone '
'from the Medicinal Herb Withania somnifera Are Covalent Inhibitors of '
'the SARS-CoV-2 Main Protease. J. Nat. Prod. 85, 2340–2350 (2022).',
'journal-title': 'J. Nat. Prod.'},
{ 'key': 'ref49',
'doi-asserted-by': 'crossref',
'first-page': 'e0125321',
'DOI': '10.1128/JVI.01253-21',
'article-title': 'Structure-Based Discovery and Structural Basis of a Novel '
'Broad-Spectrum Natural Product against the Main Protease of Coronavirus',
'volume': '96',
'author': 'Zhang Y',
'year': '2022',
'unstructured': 'Zhang, Y. et al. Structure-Based Discovery and Structural Basis of a '
'Novel Broad-Spectrum Natural Product against the Main Protease of '
'Coronavirus. J. Virol. 96, e0125321 (2022).',
'journal-title': 'J. Virol.'},
{ 'key': 'ref50',
'doi-asserted-by': 'crossref',
'first-page': '1265',
'DOI': '10.1021/acsptsci.0c00130',
'article-title': 'PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 '
'Main Protease Inhibitors',
'volume': '3',
'author': 'Ma C',
'year': '2020',
'unstructured': 'Ma, C. et al. Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and '
'Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease '
'Inhibitors. ACS Pharmacol. Transl. Sci. 3, 1265–1277 (2020).',
'journal-title': 'ACS Pharmacol. Transl. Sci.'},
{ 'key': 'ref51',
'doi-asserted-by': 'crossref',
'first-page': '4334',
'DOI': '10.1080/07391102.2020.1776157',
'article-title': 'Identification of potential natural inhibitors of SARS-CoV2 main '
'protease by molecular docking and simulation studies',
'volume': '39',
'author': 'Gupta S',
'year': '2021',
'unstructured': 'Gupta, S. et al. Identification of potential natural inhibitors of '
'SARS-CoV2 main protease by molecular docking and simulation studies. J. '
'Biomol. Struct. Dyn. 39, 4334–4345 (2021).',
'journal-title': 'J. Biomol. Struct. Dyn.'},
{ 'key': 'ref52',
'doi-asserted-by': 'crossref',
'first-page': '5989',
'DOI': '10.1021/jm300288g',
'article-title': 'Charting, navigating, and populating natural product chemical space for '
'drug discovery',
'volume': '55',
'author': 'Lachance H',
'year': '2012',
'unstructured': 'Lachance, H. et al. Charting, navigating, and populating natural product '
'chemical space for drug discovery. J. Med. Chem. 55, 5989–6001 (2012).',
'journal-title': 'J. Med. Chem.'},
{ 'key': 'ref53',
'doi-asserted-by': 'crossref',
'first-page': '485',
'DOI': '10.1007/s12298-022-01146-y',
'article-title': 'How do plants defend themselves against pathogens-Biochemical '
'mechanisms and genetic interventions',
'volume': '28',
'author': 'Kaur S',
'year': '2022',
'unstructured': 'Kaur, S. et al. How do plants defend themselves against '
'pathogens-Biochemical mechanisms and genetic interventions. Physiol. '
'Mol. Biol. Plants. 28, 485–504 (2022).',
'journal-title': 'Physiol. Mol. Biol. Plants'},
{ 'key': 'ref54',
'unstructured': 'Protein Data Bank. Retrieved August 29, 2023, from https://www.rcsb.org'},
{ 'key': 'ref55',
'doi-asserted-by': 'publisher',
'article-title': 'Crystal structure of SARS-CoV-2 Mpro in complex with the activity-based '
'probe, biotin-PEG(4)',
'author': 'Zhang L',
'year': '2020',
'unstructured': 'Zhang, L., & Hilgenfeld, R. Crystal structure of SARS-CoV-2 Mpro in '
'complex with the activity-based probe, '
'biotin-PEG(4)-Abu-Tle-Leu-Gln-vinylsulfone. '
'https://doi.org/10.2210/pdb6Z2E/pdb (2020).',
'DOI': '10.2210/pdb6Z2E/pdb'},
{ 'key': 'ref56',
'doi-asserted-by': 'crossref',
'first-page': '1331',
'DOI': '10.1126/science.abb4489',
'article-title': 'Structure-based design of antiviral drug candidates targeting the '
'SARS-CoV-2 main protease',
'volume': '368',
'author': 'Dai W',
'year': '2020',
'unstructured': 'Dai, W., Zhang, B., Jiang, X.M., Su, H., & Li, J. Structure-based design '
'of antiviral drug candidates targeting the SARS-CoV-2 main protease. '
'Science. 368, 1331–1335 (2020).',
'journal-title': 'Science.'},
{ 'key': 'ref57',
'doi-asserted-by': 'crossref',
'first-page': '1763',
'DOI': '10.1126/science.1085658',
'article-title': 'Coronavirus main proteinase (3CLpro) structure: basis for the design of '
'anti-SARS drugs',
'volume': '300',
'author': 'Anand K',
'year': '2020',
'unstructured': 'Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J.R., & Hilgenfeld, R. '
'Coronavirus main proteinase (3CLpro) structure: basis for the design of '
'anti-SARS drugs. Science. 300, 1763–1767 (2020).',
'journal-title': 'Science'},
{ 'key': 'ref58',
'doi-asserted-by': 'crossref',
'first-page': 'e0240653',
'DOI': '10.1371/journal.pone.0240653',
'article-title': 'Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease '
'inhibitors: A molecular docking and simulation studies',
'volume': '15',
'author': 'Cherrak SA',
'year': '2020',
'unstructured': 'Cherrak, S.A., Merzouk, H., & Mokhtari-Soulimane, N. Potential bioactive '
'glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A '
'molecular docking and simulation studies. PLoS One. 15, e0240653 (2020).',
'journal-title': 'PLoS One'},
{ 'key': 'ref59',
'doi-asserted-by': 'crossref',
'first-page': '5047',
'DOI': '10.1038/s41467-020-18709-w',
'article-title': 'Crystallographic and electrophilic fragment screening of the SARS-CoV-2 '
'main protease',
'volume': '11',
'author': 'Douangamath A',
'year': '2020',
'unstructured': 'Douangamath, A., Fearon, D., Gehrtz, P., Krojer, T., & Lukacik, P. '
'Crystallographic and electrophilic fragment screening of the SARS-CoV-2 '
'main protease. Nat. Commun. 11, 5047 (2020).',
'journal-title': 'Nat. Commun.'},
{ 'key': 'ref60',
'doi-asserted-by': 'crossref',
'first-page': '19',
'DOI': '10.1016/j.softx.2015.06.001',
'article-title': 'High performance molecular simulations through multi-level parallelism '
'from laptops to supercomputers',
'volume': 'GROMACS',
'author': 'Abraham MJ',
'year': '2015',
'unstructured': 'Abraham, M.J. et al. GROMACS: High performance molecular simulations '
'through multi-level parallelism from laptops to supercomputers. '
'SoftwareX. 1, 19–25 (2015).',
'journal-title': 'SoftwareX'},
{ 'key': 'ref61',
'doi-asserted-by': 'crossref',
'first-page': '2135',
'DOI': '10.1002/jcc.23354',
'article-title': 'CHARMM36 all-atom additive protein force field: validation based on '
'comparison to NMR data',
'volume': '34',
'author': 'Huang J',
'year': '2013',
'unstructured': 'Huang, J., & MacKerell, A.D. Jr. CHARMM36 all-atom additive protein '
'force field: validation based on comparison to NMR data. J. Comput. '
'Chem. 34, 2135–2145 (2013).',
'journal-title': 'J. Comput. Chem.'},
{ 'key': 'ref62',
'doi-asserted-by': 'crossref',
'first-page': '926',
'DOI': '10.1063/1.445869',
'article-title': 'Comparison of simple potential functions for simulating liquid water',
'volume': '79',
'author': 'Jorgensen WL',
'year': '1983',
'unstructured': 'Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., & Klein, '
'M.L. Comparison of simple potential functions for simulating liquid '
'water. J. Chem. Phys. 79, 926 (1983).',
'journal-title': 'J. Chem. Phys.'},
{ 'key': 'ref63',
'doi-asserted-by': 'crossref',
'first-page': '10089',
'DOI': '10.1063/1.464397',
'article-title': 'Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems',
'volume': '98',
'author': 'Darden T',
'year': '1993',
'unstructured': 'Darden, T., York, D., & Pedersen, L. Particle mesh Ewald: An N⋅log(N) '
'method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 '
'(1993).',
'journal-title': 'J. Chem. Phys.'},
{ 'key': 'ref64',
'doi-asserted-by': 'crossref',
'first-page': '435',
'DOI': '10.1111/cbdd.13653',
'article-title': 'Impact of lymphoma-linked Asn11Tyr point mutation on the interaction '
'between Bcl-2 and a BH3 mimetic: Insights from molecular dynamics '
'simulation',
'volume': '95',
'author': 'Singh K',
'year': '2020',
'unstructured': 'Singh,K. & Briggs, J.M. Impact of lymphoma-linked Asn11Tyr point '
'mutation on the interaction between Bcl-2 and a BH3 mimetic: Insights '
'from molecular dynamics simulation. Chem. Biol. Drug Design. 95, 435–450 '
'(2020).',
'journal-title': 'Chem. Biol. Drug Design.'},
{ 'key': 'ref65',
'doi-asserted-by': 'crossref',
'first-page': '3684',
'DOI': '10.1063/1.448118',
'article-title': 'Molecular dynamics with coupling to an external bath',
'volume': '81',
'author': 'Berendsen H',
'year': '1984',
'unstructured': 'Berendsen, H., Postma, J., van Gunsteren, W., DiNola, A., & Haak, J. '
'Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, '
'3684–3690 (1984).',
'journal-title': 'J. Chem. Phys.'},
{ 'key': 'ref66',
'doi-asserted-by': 'crossref',
'DOI': '10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H',
'article-title': 'E. M. LINCS: A linear constraint solver for molecular simulations',
'volume': '18',
'author': 'Hess B',
'year': '1997',
'unstructured': 'Hess, B., Bekker, H., Berendsen, H. J. C., & Fraaije, J. G. E. M. LINCS: '
'A linear constraint solver for molecular simulations. J. Comp. Chem. 18, '
'(1997).',
'journal-title': 'J. Comp. Chem.'},
{ 'key': 'ref67',
'doi-asserted-by': 'crossref',
'first-page': '33',
'DOI': '10.1016/0263-7855(96)00018-5',
'article-title': 'VMD - Visual Molecular Dynamics',
'volume': '14',
'author': 'Humphrey W',
'year': '1996',
'unstructured': 'Humphrey, W., Dalke, A., & Schulten, K. VMD - Visual Molecular Dynamics. '
'J. Mol. Graphics. 14, 33–38 (1996).',
'journal-title': 'J. Mol. Graphics.'},
{ 'key': 'ref68',
'doi-asserted-by': 'crossref',
'first-page': '1605',
'DOI': '10.1002/jcc.20084',
'article-title': 'UCSF Chimera - A visualization system for exploratory research and '
'analysis',
'volume': '25',
'author': 'Pettersen E',
'year': '2004',
'unstructured': 'Pettersen, E. et al. UCSF Chimera - A visualization system for '
'exploratory research and analysis. J. Comp. Chem. 25, 1605–1612 (2004).',
'journal-title': 'J. Comp. Chem.'},
{ 'key': 'ref69',
'volume-title': 'Protein Preparation Wizard; Epik, Schrödinger',
'author': 'Schrödinger Release 2022-4',
'year': '2022',
'unstructured': 'Schrödinger Release 2022-4: Protein Preparation Wizard; Epik, '
'Schrödinger, LLC, New York, NY, 2022.'},
{ 'key': 'ref70',
'doi-asserted-by': 'crossref',
'first-page': '1752',
'DOI': '10.1002/jcc.20292',
'article-title': 'Integrated modeling program applied chemical theory (IMPACT)',
'volume': '26',
'author': 'Banks JL',
'year': '2005',
'unstructured': 'Banks, J.L. et al. Integrated modeling program applied chemical theory '
'(IMPACT). J. Comp. Chem. 26, 1752–1780 (2005).',
'journal-title': 'J. Comp. Chem.'},
{ 'key': 'ref71',
'unstructured': 'Schrödinger Release 2022-4: Glide, Schrödinger, LLC, New York, NY, 2022'},
{ 'key': 'ref72',
'author': 'Schrödinger',
'year': '2022',
'unstructured': 'Schrödinger Release 2022-4: LigPrep, Schrödinger, LLC, New York, NY, '
'2022'},
{ 'key': 'ref73',
'doi-asserted-by': 'crossref',
'first-page': '2794',
'DOI': '10.1002/prot.23106',
'article-title': 'The VSGB 2.0 model: a next-generation energy model for high-resolution '
'protein structure modeling',
'volume': '79',
'author': 'Li J',
'year': '2011',
'unstructured': 'Li, J., Abel, R., Zhu, K., Cao, Y., Zhao, S., & Friesner RA. The VSGB '
'2.0 model: a next-generation energy model for high-resolution protein '
'structure modeling. Proteins. 79, 2794–2812 (2011).',
'journal-title': 'Proteins.'},
{ 'key': 'ref74',
'doi-asserted-by': 'crossref',
'first-page': '781',
'DOI': '10.1016/j.scitotenv.2013.06.081',
'article-title': 'Validation of quantitative structure-activity relationship models to '
'predict water-solubility of organic compounds',
'volume': '463–464',
'author': 'Cappelli CI',
'year': '2013',
'unstructured': 'Cappelli, C.I., Manganelli, S., Lombardo, A., Gissi, A., & Benfenati, E. '
'Validation of quantitative structure-activity relationship models to '
'predict water-solubility of organic compounds. Sci. Total Environ. '
'463–464, 781–789 (2013).',
'journal-title': 'Sci. Total Environ'},
{ 'key': 'ref75',
'doi-asserted-by': 'crossref',
'first-page': '31',
'DOI': '10.1517/17460441.1.1.31',
'article-title': 'In silico prediction of aqueous solubility',
'volume': '1',
'author': 'Dearden JC',
'year': '2006',
'unstructured': 'Dearden, J.C. In silico prediction of aqueous solubility. Expet Opin. '
'Drug Discov. 1, 31–52 (2006).',
'journal-title': 'Expet Opin. Drug Discov'}],
'container-title': [],
'original-title': [],
'link': [ { 'URL': 'https://www.researchsquare.com/article/rs-3888947/v1',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.researchsquare.com/article/rs-3888947/v1.html',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 1, 29]],
'date-time': '2024-01-29T10:28:52Z',
'timestamp': 1706524132000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.researchsquare.com/article/rs-3888947/v1'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 1, 29]]},
'references-count': 75,
'URL': 'http://dx.doi.org/10.21203/rs.3.rs-3888947/v1',
'relation': {},
'published': {'date-parts': [[2024, 1, 29]]},
'subtype': 'preprint'}
