TY - JOUR
T1 - Mechanistic Insights into SARS-CoV-2 Main Protease Inhibition Reveals Hotspot Residues
AU - Marimuthu, Parthiban
AU - Gorle, Suresh
AU - Karnati, Konda Reddy
N1 - Funding Information:
P.M. gratefully acknowledges the use of the bioinformatics infrastructure facility supported by Biocenter Finland, grants from the Joe, Pentti and Tor Borg Memorial Fund 2020, the Sigrid Juselius Foundation, and the CSC-IT Center for Science (Project: 2000461) for the computational facility; Dr. Jukka Lehtonen for the IT support; and Prof. Outi Salo-Ahen (Pharmacy) and Prof. Mark Johnson (SBL), Åbo Akademi University, for providing the lab support. K.R.K. acknowledges the support of Bowie State University Course-based Undergraduate Research Experience and Title III programs.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/12/27
Y1 - 2021/12/27
N2 - The main protease (Mpro) is a key enzyme responsible for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication that causes the spread of the global pandemic novel coronavirus (nCOVID-19) infection. In the present study, multiple computational approaches such as docking, long-range molecular dynamics (MD) simulations, and binding free-energy (BFE) estimation techniques were employed to investigate the mechanistic basis of the high-affinity inhibitors-GC-376, Calpain XII, and Calpain II (hereafter Calpain as Cal) from the literature-binding to Mpro. Redocking GC-376 and docking Cal XII and Cal II inhibitors to Mpro were able to reproduce all crucial interactions like the X-ray conformation. Subsequently, the apo (ligand-free) and three holo (ligand-bound) complexes were subjected to extensive MD simulations, which revealed that the ligand binding did not alter the overall Mpro structural features, whereas the heatmap analysis showed that the residues located in subsites S1 and S2, the catalytic dyad, and the 45TSEDMLN51 loop in Mpro exhibit a conformational deviation. Moreover, the BFE estimation method was used to elucidate the crucial thermodynamic properties, which revealed that Coulomb, solvation surface accessibility (Solv_SA), and lipophilic components contributed significant energies for complex formation. The decomposition of the total BFE to per-residue showed that H41, H163, M165, Q166, and Q189 residues contributed maximum energies. The overall results from the current investigation might be valuable for designing novel anti-Mpro inhibitors.
AB - The main protease (Mpro) is a key enzyme responsible for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication that causes the spread of the global pandemic novel coronavirus (nCOVID-19) infection. In the present study, multiple computational approaches such as docking, long-range molecular dynamics (MD) simulations, and binding free-energy (BFE) estimation techniques were employed to investigate the mechanistic basis of the high-affinity inhibitors-GC-376, Calpain XII, and Calpain II (hereafter Calpain as Cal) from the literature-binding to Mpro. Redocking GC-376 and docking Cal XII and Cal II inhibitors to Mpro were able to reproduce all crucial interactions like the X-ray conformation. Subsequently, the apo (ligand-free) and three holo (ligand-bound) complexes were subjected to extensive MD simulations, which revealed that the ligand binding did not alter the overall Mpro structural features, whereas the heatmap analysis showed that the residues located in subsites S1 and S2, the catalytic dyad, and the 45TSEDMLN51 loop in Mpro exhibit a conformational deviation. Moreover, the BFE estimation method was used to elucidate the crucial thermodynamic properties, which revealed that Coulomb, solvation surface accessibility (Solv_SA), and lipophilic components contributed significant energies for complex formation. The decomposition of the total BFE to per-residue showed that H41, H163, M165, Q166, and Q189 residues contributed maximum energies. The overall results from the current investigation might be valuable for designing novel anti-Mpro inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85120544713&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.1c00928
DO - 10.1021/acs.jcim.1c00928
M3 - Article
C2 - 34842417
AN - SCOPUS:85120544713
SN - 1549-9596
VL - 61
SP - 6053
EP - 6065
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 12
ER -