Allosteric Modulation of the Main Protease (MPro) of SARS-CoV-2 by Casticin—Insights from Molecular Dynamics Simulations

Abstract

Inhibition of the main protease (M pro ) of SARS-CoV-2 has been suggested to be vital in shutting down viral replication in a host. Most efforts aimed at inhibiting M Pro activity have been channeled into competitive inhibition at the active site, but this strategy will require a high inhibitor concentration and impressive inhibitor-M Pro binding affinity. Allosteric inhibition can potentially serve as an effective strategy for alleviating these limitations. In this study, the ability of antiviral natural products to inhibit M Pro in an allosteric fashion was explored with in silico techniques. Molecular docking revealed a strong interaction between casticin, an antiviral flavonoid, and M pro at a site distant from the active site. This site, characterized as a distal site, has been shown to have an interdependent dynamic effect with the active site region. M pro only, M pro -peptide (binary) and M pro -peptide-casticin (ternary) complexes were subjected to molecular dynamics simulations for 50 ns to investigate the modulatory activity of casticin binding on M pro . Molecular dynamic simulations revealed that binding of casticin at the distal site interferes with the proper orientation of the peptide substrate in the oxyanion hole of the active site, and this could lead to a halt or decrease in catalytic activity. This study therefore highlights casticin as a potential allosteric modulator of the SARS-CoV-2 main protease, which could be optimized and developed into a potential lead compound for anti-SARS-CoV-2 chemotherapy.

Design, synthesis, and in silico-in vitro antimalarial evaluation of 1,2,3-triazole-linked dihydropyrimidinone quinoline hybrids

“…This clarifies how the flexibility of the protein is impacted by ligand binding. As expected, the graphs show the high flexibility of the protein's N and C termini [39]. Although there were non-terminal residues with greater RSMF values, they were either extremely close to the terminal or very far from the protein's binding pocket, as demonstrated by Gly67 in the 10a-protein complex, which had an RMSF value of 3.29 Å.…”

“…Accidentally, no correlation was observed between the docking scores and the antiplasmodial IC 50 values of the synthesised compounds. As it is well known with competitive inhibitors, it is always a challenge to design compounds that could competitively bind at the active site with higher binding affinity than the cofactor [39]; however, rational optimisations could be a saving grace. Though all the synthesised compounds showed insignificantly lower binding affinity than the FAD cofactor, all of them displayed considerable binding energy, and five of the synthesised compounds showed higher binding affinity than the chloroquine standard.…”

Essential Oils from the Fruits and Leaves of Spondias mombin Linn.: Chemical Composition, Biological Activity, and Molecular Docking Study

“…Prior to docking, the protein was prepared using AutoDockTools-1.5.7rc1. Cocrystallized ligands and water molecules were removed, Gasteiger charges were calculated for atoms, and polar hydrogens were added [ 33 ]. The output file was saved in the pdbqt format.…”

N-alkylimidazole derivatives as potential inhibitors of quorum sensing in Pseudomonas aeruginosa

“…Ligands were further prepared for docking by adding polar hydrogens, merging non-polar hydrogens, and calculating Gasteiger charges for all atoms. The crystal structure of LasR, co-crystallized with the native substrate N-3-oxo-dodecanoyl- l -homoserine lactone, and a quorum sensing anti-activator protein AQS1 [ 28 ] was downloaded from the Protein Data Bank with the code 6V7X and a resolution of 2.90 Å. AutoDockTools-1.5.7rc136 was used to prepare the protein for docking by removing crystallographic water molecules and co-crystallized ligands, adding polar hydrogens and calculating Gasteiger charges for all receptor atoms [ 29 , 30 ].…”