Structure-Based Virtual Screening to Discover Potential Lead Molecules for the SARS-CoV-2 Main Protease

Abstract

The COVID-19 disease is caused by a new strain of the coronavirus family (SARS-CoV-2), and it has affected at present millions of people all over the world. The indispensable role of the main protease (M pro ) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 M pro as a proposition to halt virus ingression is being pursued by scientists globally. Here we carried out a study with two objectives: the first being to perform comparative protein sequence and 3D structural analysis to understand the effect of 12 point mutations on the active site. Among these, two mutations, viz., Ser46 and Phe134, were found to cause a significant change at the active sites of SARS-CoV-2. The Ser46 mutation present at the entrance of the S5 subpocket of SARS-CoV-2 increases the contribution of other two hydrophilic residues, while the Phe134 mutation, present in the catalytic cysteine loop, can cause an increase in catalytic efficiency of M pro by facilitating fast proton transfer from the Cys145 to His41 residue. It was observed that active site remained conserved among M pro of both SARS-CoVs, except at the entrance of the S5 subpocket, suggesting sustenance of substrate specificity. The second objective was to screen the inhibitory effects of three different data sets (natural products, coronaviruses main protease inhibitors, and FDA-approved drugs) using a structure-based virtual screening approach. A total of 73 hits had a combo score >2.0. Eight different structural scaffold classes were identified, such as one/two tetrahydropyran ring(s), dipeptide/tripeptide/oligopeptide, large (approximately 20 atoms) cyclic peptide, and miscellaneous. The screened hits showed key interactions with subpockets of the active site. Further, molecular dynamics studies of selected screened compounds confirmed their perfect fitting into the subpockets of the active site. This study suggests promising structures that can fit into the SARS-CoV-2 M pro active site and also offers direction for further lead optimization and rational drug design.

Nature as a Treasure Trove for Anti-COVID-19: Luteolin and Naringenin from Indonesian Traditional Herbal Medicine Reveal Potential SARS-CoV-2 Mpro Inhibitors Insight from in Silico Studies

“…It was also noticed that the catalytic dyad residue Cys145 stabilised via HB and pi-alkyl interaction. Luteolin also exhibited interaction with S1 (Gly143, Cys145, His163, and Glu166), S2 (His41 and Cys145), S3 (His41, Met49, and Met165), S4 (Met165 and Glu166), and S5 (Met165, Glu166 and Gln189) 8,17,51 . From this result, it is clear that both bioactive phytochemicals, Luteolin and Naringenin have interactions with the active site and substrate-binding pocket located between the clefts of domain I and II of the 3CL pro .…”

“…Furthermore, it was noticed that the HB of Cys145 residue strengthens by the establishment of pi-alky interaction. Furthermore, it also interacted with several important residues required for the substrate-binding pocket designated as S1 (Gly143, Cys145, and Glu166), S2 (His41and Cys145), S3 (His41, Met49, and Met165), S4 (Met165 and Glu166), and S5 (Met165, Glu166, and Gln189) 8,17,51 .…”

“…Structurally, there are more 20 proteins encoded by the genome of this virus, which comprises the 3C-like protease (3CL pro or M pro ), which shares a higher similarity with SARS-CoV than to MERS-CoV [7][8][9] . The 3CL pro is a homodimer, comprising two protomers, and a catalytic dyad site constructed by Cys145 and His41 residues, established among the domain I and II ( Figure 1) 10,11 .…”

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

“…Both drugs demonstrated micromolar activity in vitro [ 10 ]. Broader virtual screening campaigns have been undertaken, some involving many hundreds of millions of compounds [ 152 ], and also targeting mutations naturally occurring in the binding site of SARS-CoV-2 3CLpro [ 153 ]. Potential hit compounds are currently being experimentally confirmed.…”

Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein

“…3 In the current context and given the recent developments regarding clinical trial results, the urge to identify new drugs for the effective treatment of COVID-19 is particularly strong, and computational drug repurposing appears a relevant route. 4 In this direction, a number of virtual screening studies have emerged in peer-reviewed and renowned online archives, aiming mostly at two major targets: i.e., the active site of the main protease [5][6][7][8][9][10][11][12][13][14][15] and the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2. The 3-chymotrypsin-like protease (3CL-PR) and the RNA-dependent-RNA polymerase (RdRp) were also suggested to be druggable targets.…”