Abstract
The main protease enzyme (M pro ) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the M pro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with K i values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.
Keywords: Mpro; SARS-CoV-2; allosteric inhibitor; aryl nitrile; docking; structure-based virtual screening.
【저자키워드】 SARS-CoV-2, docking, MPro, structure-based virtual screening., Allosteric inhibitor, aryl nitrile, 【초록키워드】 COVID-19, Treatment, Virtual screening, protease, COVID-19 treatments, Characteristics, target, inhibitor, mechanism, binding, Ligand, assessments, enzyme, medium, Compound, M pro, candidate, selected, carried, suggested, 【제목키워드】 Screening, Biological, Site, the SARS-CoV-2,