Exploration of SARS-CoV-2 Mpro Noncovalent Natural Inhibitors Using Structure-Based Approaches

Abstract

With the emergence of antibody-evasive omicron subvariants (BA.2.12.1, BA.4, and BA.5), which can compromise the efficacy of vaccination, it is of utmost importance to widen the finite therapeutic options for COVID-19. Although more than 600 co-crystal complexes of Mpro with inhibitors have been revealed, utilizing them to search for novel Mpro inhibitors remains limited. Although there were two major groups of Mpro inhibitors, covalent and noncovalent inhibitors, noncovalent inhibitors were our main focus due to the safety concerns with their covalent counterparts. Hence, this study aimed to explore Mpro noncovalent inhibition ability of phytochemicals extracted from Vietnamese herbals by combining multiple structure-based approaches. By closely inspecting 223 complexes of Mpro with noncovalent inhibitors, a 3D-pharmacophore model representing typical chemical features of Mpro noncovalent inhibitors was generated with good validation scores (sensitivity = 92.11%, specificity = 90.42%, accuracy = 90.65%, and goodness-of-hit score = 0.61). Afterward, the pharmacophore model was applied to explore the potential Mpro inhibitors from our in-house Vietnamese phytochemical database, revealing 18 substances, 5 of which were in vitro assayed. The remaining 13 substances were then examined by induced-fit molecular docking, revealing 12 suitable compounds. A machine-learning activity prediction model was developed to rank the hit, suggesting nigracin and calycosin-7-O-β-glucopyranoside as promising Mpro natural noncovalent inhibitors.

Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation

“…Another important residue that interacts with all selected flavonoids is Glu166, a key amino acid involved in the dimerization of the Mpro protein and assists in creating the S1 substrate binding pocket ( Goyal and Goyal, 2020 ; Silvestrini et al, 2021 ). The formation of a hydrogen bond with the Glu166 residue is reported in the study by Duong and Nguyen ( Duong and Nguyen, 2023 ) as one of the key interactions of non-covalent Mpro inhibitors. It is interesting to note that the crystallographic inhibitor 3WL, used as a reference in this study, also formed a hydrogen bond with the Glu166 residue, which corroborates our results ( Su et al, 2020 ).…”

Consensus Pharmacophore Strategy For Identifying Novel SARS-Cov-2 Mpro Inhibitors from Large Chemical Libraries

“…Recent studies have discovered various M pro inhibitors, − such as ensitrelvir (S-217622), a nonpeptidic inhibitor developed through virtual screening and drug design, and Pfizer’s nirmatrelvir, which effectively treats COVID-19 when used with ritonavir. , Other M pro inhibitors have been discovered using molecular docking, − molecular dynamics, − QSAR, − ligand-based design, − and pharmacophore-matching. − …”

“… 24 , 25 Other M pro inhibitors have been discovered using molecular docking, 26 − 29 molecular dynamics, 30 − 32 QSAR, 33 − 35 ligand-based design, 36 − 39 and pharmacophore-matching. 40 − 43 …”