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Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach

Singh et al., Research Square, doi:10.21203/
Jan 2024  
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Quercetin for COVID-19
24th treatment shown to reduce risk in July 2021
*, now known with p = 0.0031 from 11 studies.
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3,800+ studies for 60+ treatments.
In Silico and In Vitro study including quercetin and curcumin derivatives as potential SARS-CoV-2 main protease (Mpro) inhibitors. Molecular dynamics simulations and virtual screening identified quercetin and curcumin derivatives demethoxycurcumin and hexahydrocurcumin as potential binders of Mpro. Demethoxycurcumin was tested in vitro, showing significant inhibitory activity against SARS-CoV-2, with no cytotoxicity observed.
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spike Note A, Alavi, Azmi (B), Chandran, Kandeil, Mandal, Moschovou, Nguyen, Pan, Thapa (B), Şimşek, Mpro Note B, Akinwumi, Alanzi, Ibeh, Kandeil, Mandal, Moschovou, Nguyen, Qin, Rehman, Sekiou (B), Singh, Thapa (B), Wang, RNA-dependent RNA polymerase Note C, Corbo, PLpro Note D, Ibeh, ACE2 Note E, Chandran, Ibeh, Qin, Thapa (B), Şimşek, Alkafaas, TMPRSS2 Note F, Chandran, helicase Note G, Alanzi, Singh (B), endoribonuclease Note H, Alavi, cathepsin L Note I, Ahmed, Wnt-3 Note J, Chandran, FZD Note K, Chandran, LRP6 Note L, Chandran, ezrin Note M, Chellasamy, ADRP Note N, Nguyen, NRP1 Note O, Şimşek, PTGS2 Note P, Qin, HSP90AA1 Note Q, Qin, matrix metalloproteinase 9 Note R, Sai Ramesh, IL-6 Note S, Yang, Yang (B), IL-10 Note T, Yang, VEGFA Note U, Yang (B), and RELA Note V, Yang (B) proteins. In Vitro studies demonstrate efficacy in Calu-3 Note W, DiGuilio, A549 Note X, Yang, HEK293-ACE2+ Note Y, Singh (C), Huh-7 Note Z, Pan, Caco-2 Note AA, Roy, Vero E6 Note AB, Kandeil, El-Megharbel, Roy, mTEC Note AC, Wu, and RAW264.7 Note AD, Wu cells. Animal studies demonstrate efficacy in K18-hACE2 mice Note AE, Aguado, rats El-Megharbel (B), and db/db mice Note AF, Wu, Wu (B).
Study covers curcumin and quercetin.
Singh et al., 29 Jan 2024, preprint, 7 authors. Contact:
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperQuercetinAll
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
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..
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-x
Dai, 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.v1
Khanna, 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/pdb
Zhang, 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
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