Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease. Issue 15 (2nd September 2021)

• Record Type: Journal Article
• Authors: Andrianov, Alexander M.; Kornoushenko, Yuri V.; Karpenko, Anna D.; Bosko, Ivan P.; Tuzikov, Alexander V.
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 39:Issue 15(2021)
• Page Start: 5779
• Page End: 5791
• Publication Date: 2021-09-02
• Subjects: Coronavirus SARS-CoV-2 -- COVID-19 -- main protease -- SARS-CoV-2 inhibitors -- virtual screening -- molecular docking -- quantum chemical calculations -- antiviral drugs; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2020.1792989
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: A computational approach to in silico drug discovery was carried out to identify small drug-like compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (M Pro ). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-M Pro structure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 M Pro were generated by molecular docking, quantum chemical calculations and molecular dynamics simulations. At the final point, analysis of the interaction modes of the identified compounds with M Pro and prediction of their binding affinity were carried out. Calculation revealed 5 top-ranking compounds that exhibited a high affinity to the active site of SARS-CoV-2 M Pro . Insights into the ligand − M Pro models indicate that all identified compounds may effectively block the binding pocket of SARS-CoV-2 M Pro, in line with the low values ​​of binding free energy and dissociation constant. Mechanism of binding of these compounds to M Pro is mainly provided by van der Waals interactions with the functionally important residues of the enzyme, such as His-41, Met-49, Cys-145, Met-165, and Gln-189 that play a role of the binding hot spots assisting the predicted molecules to effectively interact with the M Pro active site. The data obtained show that the identified X77-mimetic candidates may serve as good scaffolds for the design of novel antiviral agents able to target the active site of SARS-CoV-2 M Pro . Communicated by Ramaswamy H. Sarma