Computational Identification of Possible Allosteric Sites and Modulators of the SARS-CoV-2 Main Protease

Abstract

In this study, we target the main protease (Mpro) of the SARS-CoV-2 virus as it is a crucial enzyme for viral replication. Herein, we report three plausible allosteric sites on Mpro that can expand structure-based drug discovery efforts for new Mpro inhibitors. To find these sites, we used mixed-solvent molecular dynamics (MixMD) simulations, an efficient computational protocol that finds binding hotspots through mapping the surface of unbound proteins with 5% cosolvents in water. We have used normal mode analysis to support our claim of allosteric control for these sites. Further, we have performed virtual screening against the sites with 361 hits from Mpro screenings available through the National Center for Advancing Translational Sciences (NCATS). We have identified the NCATS inhibitors that bind to the remote sites better than the active site of Mpro, and we propose these molecules may be allosteric regulators of the system. After identifying our sites, new X-ray crystal structures were released that show fragment molecules in the sites we found, supporting the notion that these sites are accurate and druggable.

SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations

“…These studies revealed sites other than the catalytic active sites with favorable free energies of binding that overlapped the values obtained by docking the same ligands into the active sites. Furthermore, these results were in agreement with recent reports of allosteric binding sites in Mpro [ 34 , 35 ]. Because allosteric sites have been less explored than catalytic sites and allosteric binding could furnish new avenues for modulating the activity of Mpro [ 36 ], discovery of allosteric binding sites was incorporated into the present work.…”

Molecular interactions and inhibition of the SARS‐CoV‐2 main protease by a thiadiazolidinone derivative

“…However, in our work, we also report on a residue community analysis of the enzyme, which notably suggested that CCG‐50014 disrupted inter‐community correlations stemming for the catalytic residues C145 and H41. These observations highlight the role of allostery in this enzyme, which could prove useful in designing potential therapeutics targeting the enzyme via an allosteric mechanism 75–77 …”

“…These observations highlight the role of allostery in this enzyme, which could prove useful in designing potential therapeutics targeting the enzyme via an allosteric mechanism. 75 , 76 , 77 …”

Allosteric Hotspots in the Main Protease of SARS-CoV-2

“…Encouragingly, following the very recent surge of research around the M pro of SARS-CoV-2, some experimental studies have found drugs and small fragments that bind to sites other than the substrate binding site on this protein, and that might have implications for allosteric regulation [29] , [30] . Preliminary studies have also simulated binding events to distant areas of the protein by using docking and molecular dynamics (MD) [31] , [32] , [33] , MD [34] , [35] , [36] , [37] , [38] or elastic network models (ENMs) [39] , [40] . Moreover, there have already been indications of allosteric processes mediated by the extra domain in the protease of the old SARS-CoV [41] , [42] , [43] , [15] .…”