Structure-based virtual identification of natural inhibitors of SARS-CoV-2 and its Delta and Omicron variant proteins
Abdullah R Alanzi, Mohammad K Parvez, Mohammed S Al-Dosari
Future Virology, doi:10.2217/fvl-2022-0184
Aim: Structure-based identification of natural compounds against SARS-CoV-2, Delta and Omicron target proteins. Materials & methods: Several known antiviral natural compounds were subjected to molecular docking and MD simulation against SARS-CoV-2 Mpro, Helicase and Spike, including Delta and Omicron Spikes. Results: Of the docked ligands, 20 selected for each complex exhibited overall good binding affinities (-7.79 to -5.06 kcal/mol) with acceptable physiochemistry following Lipinski's rule. Finally, two best ligands from each complex upon simulation showed structural stability and compactness. Conclusion: Quercetin-3-acetyl-glucoside, Rutin, Kaempferol, Catechin, Orientin, Obetrioside and Neridienone A were identified as potential inhibitors of SARS-CoV-2 Mpro, Helicase and Spike, while Orientin and Obetrioside also showed good binding affinities with Omicron Spike. Catechin and Neridienone A formed stable complexes with Delta Spike. Plain language summary: Mutant strains of SARS-CoV-2 called 'variants of concern' (VOCs) are linked to a good ability to infect, re-infect and spread among people. They are also linked to poor ability to fight the disease and reduced effectiveness of vaccines. Delta and Omicron are important VOCs because they are difficult to control and treat. Specific resistance to some drugs used to treat COVID-19 poses a further challenge. Therefore, discovering natural or plant-derived drugs with no known resistance would be valuable to the treatment of COVID-19. In this study, we screen and identify seven plantderived compounds that may be useful to treating COVID-19 -we identify Quercetin-3-acetyl-glucoside, Rutin, Kaempferol, Catechin, Orientin, Obetrioside and Neridienone A as potential candidates. Orientin, Obetrioside, Catechin and Neridienone A are identified as candidates against Delta and Omicron for the first time.
Financial & competing interests disclosure The authors acknowledge the Researchers Supporting Project (no. RSP2023R379), King Saud University, Riyadh, Saudi Arabia for funding this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
References
Aa, Rutin as a promising inhibitor of main protease and other protein targets of COVID-19: in silico study, Nat. Prod Commun
Agrawal, Agrawal, Blunden, Rutin: A Potential Antiviral for Repurposing as a SARS-CoV-2 Main Protease (Mpro) Inhibitor, Nat. Prod. Comm
Bai, Wang, Zhao, Bioactive pregnanes from Nerium oleander, J. Nat. Prod
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
Case, Aktulga, Belfon, Amber 2021: Reference Manual
Case, Cheatham, Darden, The Amber biomolecular simulation programs, J. Comput. Chem
Chandel, Raj, Rathi, In silico identification of potent COVID-19 main protease inhibitors from FDA approved antiviral compounds and active phytochemicals through molecular docking: a drug repurposing approach,
doi:10.20944/preprints202003.0349.v1Chattopadhyay, Sarkar, Chatterjee, Recent advancements for the evaluation of antiviral activities of natural products, N. Biotechnol
Chen, Liu, Guo, Emerging coronaviruses: genome structure, replication, and pathogenesis, J. Med. Virol
Cherrak, Merzouk, Mokhtari-Soulimane, Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: a molecular docking and simulation studies, PLOS One
Corona, Wycisk, Talarico, Natural compounds inhibit SARS-CoV-2 nsp13 unwinding and ATPase enzyme activities
Da Silva, Barreira, Oliveira, Natural phytochemicals and probiotics as bioactive ingredients for functional foods: extraction, biochemistry and protected-delivery technologies, Trends Food Sci. Tech
Dinda, Dinda, Dinda, Chakraborty, Some natural compounds and their analogues having potent anti-SARS-CoV-2 and anti-proteases activities as lead molecules in drug discovery for COVID-19, Eur. J. Med. Chem. Rep,
doi:10.1016/j.ejmcr.2022.100079Duan, Wu, Chowdhury, A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations, J. Comput. Chem
Elmezayen, Al-Obaidi, Sahin, Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes
Friesner, Banks, Murphy, Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J. Med. Chem
Grant, Skjaerven, Yao, The Bio3D packages for structural bioinformatics, Prot. Sci
Harvey, Carabelli, Jackson, SARS-CoV-2 variants, Spike mutations and immune escape, Nat. Rev. Microbiol
Hillary, Ceasar, An update on COVID-19: SARS-CoV-2 variants, antiviral drugs, and vaccines, Heliyon
Hirabara, Serdan, Gorjao, SARSCOV-2 variants: differences and potential of immune evasion, Front. Cell. Infect. Microbiol,
doi:10.3389/fcimb.2021.781429Humphrey, Dalke, Schulten, VMD: visual molecular dynamics, J Mol Graph
Huynh, Wang, Luan, Structure-based lead optimization of herbal medicine rutin for inhibiting SARS-CoV-2's main protease, Phys. Chem. Chem. Phys
Infusino, Marazzato, Mancone, Diet supplementation, probiotics, and nutraceuticals in SARS-CoV-2 infection: a scoping review, Nutrients
Khan, Heng, Wang, In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro), Phytother. Res
Kim, Nichols, Wang, Mccammon, Effects of histidine protonation and rotameric states on virtual screening of M. tuberculosis RmlC, J. Comput. Aided Mol. Des
Ligprep, Ligprep, None
Mali, Chaudhari, Computational studies on imidazo [1, 2-a] pyridine-3-carboxamide analogues as antimycobacterial agents: common pharmacophore generation, atom-based 3D-QSAR, molecular dynamics simulation, QikProp, molecular docking and prime MMGBSA approaches, Open Pharm. Sci. J
Mangiavacchi, Botwina, Menichetti, Seleno-functionalization of quercetin improves the non-covalent inhibition of Mpro and its antiviral activity in cells against SARS-CoV-2, Int. J. Mol. Sci
Ohishi, Hishiki, Baig, Epigallocatechin gallate (EGCG) attenuates severe acute respiratory coronavirus disease 2 (SARS-CoV-2) infection by blocking the interaction of SARS-CoV-2 spike protein receptor-binding domain to human angiotensin-converting enzyme 2, PLOS One
Orgensen, Chandrasekhar, Madura, Impey, Klein, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys
Padhan, Parvez, Ms, Comparative sequence analysis of SARS-CoV-2 suggests its high transmissibility and pathogenicity, Future Virol,
doi:10.2217/fvl-2020-0204Pan, Lezama-Davila, Ap, Sterols with antileishmanial activity isolated from the roots of Pentalinon andrieuxii, Phytochemistry
Parvez, Ahmed, Ms, Novel Anti-Hepatitis B Virus Activity of Euphorbia schimperi and Its Quercetin and Kaempferol Derivatives, ACS Omega
Parvez, Al-Dosari, Abdelwahid, Alqahtani, Alanzi, Novel anti-hepatitis B virus-active catechin and epicatechin from Rhus tripartita, Exp. Ther. Med
Parvez, Jagirdar, Purty, COVID-19 pandemic: understanding the emergence, pathogenesis and containment (Review), World Acad. Sci. J
Parvez, Rehman, Alam, Ms, Alqasoumi et al., Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: cell culture and molecular docking study, Saudi Pharm. J
Phillips, Hardy, Maia, Scalable molecular dynamics on CPU and GPU architectures with NAMD, J. Chem. Phys,
doi:10.1063/5.0014475Pierro, Iqtadar, Khan, Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial, Int. J. Gen. Med
Pinzi, Rastelli, Molecular docking: shifting paradigms in drug discovery, Int. J. Mol. Sci
Reiberger, Radilová, Krá Ľ M, Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors, Int. J. Mol. Sci
Ren, Wang, Wu, Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study, Chin. Med. J
Runfeng, Yunlong, Jicheng, Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2), Pharmacol. Res,
doi:10.1016/j.phrs.2020.104761Sachse, Tenorio, De Castro, Unraveling the antiviral activity of plitidepsin against SARS-CoV-2 by subcellular and morphological analysis, Antiviral Res,
doi:10.1016/j.antiviral.2022.105270Schwarz, Sauter, Wang, Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus, Planta Med
Sharma, Bhardwaj, Singh, Rajendran, Purohit et al., An in-silico evaluation of different bioactive molecules of tea for their inhibition potency against nonstructural protein-15 of SARS-CoV-2, Food Chem,
doi:10.1016/j.foodchem.2020.128933Shivakumar, Harder, Damm, Friesner, Sherman, Improving the prediction of absolute solvation free energies using the next generation OPLS force field, Chem. Theory Comput
Sivakumar, Anuragh, Kammala, Ilango, Computer aided drug design approach to screen phytoconstituents of Adhatoda vasica as potential inhibitors of SARS-CoV-2 Main Protease enzyme, Life (Basel)
Sulaiman, Zarubaev, Samudi, Natural products from medicinal plants in Asia and the Pacific for RNA viruses: hercules' fifth labour, Pharm. Biol
Versiani, Ahmed, Ikram, Ali, Yasmeen et al., Chemical constituents and biological activities of Adenium obesum (Forsk.) Roem. et Schult, Chem. Biodiver
Vrijsen, Everaert, Boeye, Antiviral activity of flavones and potentiation by ascorbate, J. Gen. Virol
Wahab, Aboelmaaty, Lahloub, Sallam, In vitro and in silico studies of SARS-CoV-2 main protease Mpro inhibitors isolated from Helichrysum bracteatum, RSC Adv
Walls, Park, Tortorici, Wall, Mcguire et al., Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein, Cell
Wan, Xiang, Fang, Clinical features and treatment of COVID-19 patients in northeast Chongqing
Wan, Xiang, Fang, Clinical features and treatment of COVID-19 patients in northeast Chongqing, J. Med. Virol
Wang, Zhang, Wang, Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions, Sig. Transduct. Target Ther
Weinzierl, Molecular dynamics simulations of human FOXO3 reveal intrinsically disordered regions spread spatially by intramolecular electrostatic repulsion, Biomolecules
Wu, Liu, Yang, Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods, Acta Pharm. Sin. B
Yan, Zheng, Zeng, He, Cheng, Structural biology of SARS-CoV-2: open the door for novel therapies, Sig. Transduct. Target Ther
Ziebuhr, Molecular biology of severe acute respiratory syndrome coronavirus, Curr. Opin. Microbiol
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