Insights into the binding and covalent inhibition mechanism of PF-07321332 to SARS-CoV-2 M^pro

Abstract

The catalytic triad Cys145–His41–Asp187 of SARS-CoV-2 Mpro plays an important role in the activation of the PF-07321332 covalent inhibitor.

Characterizing the ligand-binding affinity toward SARS-CoV-2 Mproviaphysics- and knowledge-based approaches

“…A small constant force of 1 kcal mol À1 nm À2 was applied to pull the sulfur atom of the Cys145 residue and the nitrile group of PF-07321332 together because they can adopt a covalent bond. 83 During calculations, SARS-CoV-2 Mpro translational and rotational degrees of freedom were restrained by using a small harmonic potential applied on C a atoms of the protease. 83 Over 81 trajectories, the binding pose between SARS-CoV-2 Mpro and PF-07321332 was found, and the stable binding structures were probed.…”

Searching for potential inhibitors of SARS-COV-2 main protease using supervised learning and perturbation calculations

“…As mentioned above, the catalytic triad Cys145-His41-Asp187 may play a crucial role in the binding process of a ligand to SARS-CoV-2 Mpro [75] . The distance between the Cys145-Sγ and His41-Nε ( ) and His41-Nδ vs. Asp187-Oδ ( ) atoms was considered to mediate the influence of ligands on SARS-CoV-2 Mpro.…”

“…In particular, the Amber99SB-iLDN force field [74] was employed to topologize the protease and charge-neutralizing ions. The catalytic triad Cys145-His41-Asp187 may play a vital role in the binding process of a ligand to SARS-CoV-2 Mpro [75] . The protonation state of these residues was assigned as shown in Figure 1 C .…”

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

“…On the other hand, it has been evidenced that the P3 and P4 groups (isobutyl and trifluoromethyl) made a favorable but small contribution to the binding free energy, suggesting the possibility of modification on these sites to increase the binding strength. 91 , 92 …”

“…It has been demonstrated that P1 (γ-lactamic ring) and the P2 (dimethyl-cyclopropylproline group) are essential in the ligand-binding process, contributing positively to the total binding free energy (substitution with other groups determined a drastic reduction of binding affinity). On the other hand, it has been evidenced that the P3 and P4 groups (isobutyl and trifluoromethyl) made a favorable but small contribution to the binding free energy, suggesting the possibility of modification on these sites to increase the binding strength. , …”