SEARCH FOR STRUCTURAL SCAFFOLDS AGAINST SARS-COV-2 MPRO: AN IN SILICO STUDY
DOI:
https://doi.org/10.4314/jfas.v13i2.7Keywords:
SARS-CoV-2, COVID-19, Mpro, in silico techniques, structural scaffolds, ligand-protein interactionAbstract
The emergence of the deadly SARS-CoV-2, the etiologic agent of COVID-19 towards the end of the fourth quarter of 2019 has necessitated intensive research towards the development of drugs and vaccine that can combat the disease. Consequently, we conducted molecular docking of the e-Drug3D library using London dG and Affinity dG as scoring algorithms for common structural scaffolds in drug molecules with strong binding affinities towards SARS-CoV-2 Mpro. 15 drug molecules forming about 0.8% of the library bound strongly to the target protein, which gave rise to Two potential structural scaffolds: (4S,4aR,5aR,12aS)-4-(dimethylamino)-10,12,12a-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide and the stilbenoid-like structure. These scaffolds could serve as potential starting points in the structure-based design of anti-SARS-CoV-2 drugs.
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References
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[6] Kandeel M, Al-Nazawi M. Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease, Life Sci, 2020, 251, 117627, doi: 10.1016/j.1fs.2020.117627.
[7] Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zheng X, Yang Y, Li X, Zhang X, et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. Proc. Natl. Acad. Sci. USA 2020, 117, 10970-10975, doi: 10.1073/pnas.2005615117.
[8] Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020, 30, 269 – 271, doi: 10.1038/s41422-020-0282-0.
[9] Ullrich S, Nitsche C. The SARS-CoV-2 main protease as drug target. Bioorganic & Medicinal Chemistry Letters, 2020, 30, 127377. doi: 10.1016/j.bmcl.2020.127377.
[10] Gimeno A, Mestres-Truyol J, Ojeda-Montes M J, Macip G, Saldivar-Espinoza B, Cereto-Massague A, Pujadas G, Garcia-Vallve S. Prediction of novel inhibitors of the main protease (M-pro) of SARS-CoV-2 through consensus docking and drug reposition. Int. J. Mol. Sci. 2020, 21, 3793, doi: 10.3390/ijms21113793.
[11] Ren Z, Yan, L, Zhang N, Guo Y, Yang C, Lou R Z. The newly emerged SARS-like coronavirus HCoV-EMC also has an “Achilles’ heel”: Current effective inhibitor targeting a 3C-like protease. Protein Cell 2013, 4(4): 248-250, doi: 10.1007/s13238-013-2841-3.
[12] Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 2020, 368, 409-412, doi: 10.1126/science.abb3405.
[13] Tang B, He F, Liu D, Fang M, Wu Z, Xu D. AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2. bioRxiv 2020, doi: 10.1101/2020.03.03.972133.
[14] Fischer A, Sellner M, Neranjan S, Smiesko M, Lill M A. Potential inhibitors for novel Coronavirus protease identified by virtual screening of 606 million compounds. Int. J. Mol. Sci. 2020, 21, 3626, doi: 10.3390/ijms21103626.
[15] Ton A T, Gentile F, Hsing M, Ban F, Cherkasov A. Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease by Deep Docking of 1.3 Billion Compounds. Mol. Inform. 2020, 39(8), 2000028, doi: 10.1002/minf.202000028.
[16] Ou-Yang S S, Lu J Y, Kong X Q, Liang Z J, Luo C, Jiang H. Computational drug discovery. Acta. Pharmacol. Sin., 2012, 33(9), 1131-1140, doi: 10.1038/aps.2012.109.
[17] Douguet D. Data Sets Representative of the Structures and Experimental Properties of FDA-Approved Drugs. ACS Med. Chem. Lett. 2018, 9(3), 204-209, doi: 10.1021/acsmedchemlett.7b00462.
[18] Berman H M, Westbrook J, Feng Z, Gilliland G, Bhat T N, Weissig H, Shindyalov I N, Bourne P E. The protein data bank. Nucleic Acids Res. 2000, 28(1), 235-342, doi: 10.1093/nar/28.1.235.
[19] Molecular Operating Environment, version 2014; Chemical Computing Group Inc: Montreal, Canada, 2010.
[20] Halgren T A. Merck molecular forcefield. J. Comput. Chem. 1996, 17, 490-641, doi: 10.1002/(SICI)1096-987X(199604)17:5/6<520::AID-JCC2>3.0.CO;2-W.
[21] Anand K, Palm G J, Mesters J R, Siddell S G, Ziebuhr J, Hilgenfeld R. Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra alphahelical domain, EMBO J. 2002, 21(13), 3213-3224.
[22] Yoshino R, Yasuo N, Sekijima M. Identification of key interactions between SARS-CoV-2 main protease and inhibitor drug candidate. Scientific Reports, 2020, 10, 12493, doi: 10.1038/s41598-020-69337-9.
[23] Gentile D, Patamiia V, Scala A, Sciortino M T, Piperno A, Rescifina A. Putative Inhibitors of SARS-CoV-2 Main Protease from A Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study. Mar. Drugs 2020, 18, 225, doi: 10.3390/md18040225.
[24] Arun, K G, Sharanya C S, Abhithaj J, Francis D, Sadasivan C. Drug repurposing against SARS-CoV-2 using E-pharmacophore based virtual screening, molecular docking and molecular dynamics with main protease as the target. J. Biomol. Struct. Dyn. 2020, doi: 10.1080/07391102.2020.1779819.
[25] Ntie-Kang F, Nwodo N J, Ibezim A, Simoben C V, Karaman B, Ngwa V F, Sippl W, Adikwu U M, Mbaze L M. Molecular modeling of potential anticancer agents from African medicinal plants. J. Chem. Inf. Model. 2014, 54, 2433-2450, doi: 10.1021/ci5003697.
[26] DrugBank. Available online: https://www.drugbank.ca/drugs/ (Assessed on 25 August, 2020).
[27] Lipinski C A, Lombardo F, Dominy B W, Feeney P J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2001, 46(1-3), 3-26, doi: 10.1016/S0169-409X(00)00129-0.
[28] Leeson P D, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov. 2007, 6(11): 881-890. doi: 10.1038/nrd2445.
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Published
2021-01-10
How to Cite
ONAH, E.; UGWOKE, I. C.; EZE, U. J.; EZE, H. C.; MUSA, S. K.; NDIANA-ABASI, S.; OKOLI, O.; EKEH, I. E.; EDET, A. A. SEARCH FOR STRUCTURAL SCAFFOLDS AGAINST SARS-COV-2 MPRO: AN IN SILICO STUDY. Journal of Fundamental and Applied Sciences, [S. l.], v. 13, n. 2, p. 740–769, 2021. DOI: 10.4314/jfas.v13i2.7. Disponível em: https://www.jfas.info/index.php/JFAS/article/view/987. Acesso em: 13 may. 2026.
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