Contribution of the catalytic dyad of SARS-CoV-2 main protease to binding covalent and noncovalent inhibitors.

ABSTRACT: The effect of mutations of the catalytic dyad residues of SARS-CoV-2 main protease (MPro^WT) on the thermodynamics of binding of covalent inhibitors comprising nitrile [nirmatrelvir (NMV), NBH2], aldehyde (GC373), and ketone (BBH1) warheads to MPro is examined together with room temperature X-ray crystallography. When lacking the nucleophilic C145, NMV binding is ∼400-fold weaker corresponding to 3.5 kcal/mol and 13.3 °C decrease in free energy (ΔG) and thermal stability (T_m), respectively, relative to MPro^WT. The H41A mutation results in a 20-fold increase in the dissociation constant (K_d), and 1.7 kcal/mol and 1.4 °C decreases in ΔG and T_m, respectively. Increasing the pH from 7.2 to 8.2 enhances NMV binding to MPro^H41A, wh

SUBMITTER: Kovalevsky A 

PROVIDER: S-EPMC10238122 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature