Molecular dynamic simulations to explore the broad-spectrum activity of the inhibitor PF-07321332 against human...

The main protease (M^pro) stands as a pivotal enzyme crucial for coronavirus replication, thus serving as a prime target for coronavirus drug discovery endeavors. Nirmatrelvir (PF-07321332), an antiviral compound developed by Pfizer, has been engineered to selectively inhibit the M^pro of SARS-CoV-2 by directly binding to its catalytic cysteine residue (Cys145). In a bid to scrutinize the expansive inhibitory spectrum of PF-07321332 against a gamut of human pathogenic coronaviruses, we undertook an exhaustive investigation leveraging molecular dynamics (MD) simulations in conjunction with binding free energy (BFE) calculations. Molecular dockings of PF-07321332 with the M^pros of seven human coronaviruses yielded their optimal binding modes (complexes), subsequently subjected to rigorous MD simulations and BFE assessments. The results of MD simulations indicated that PF-07321332 can remain stable in the substrate-binding cavity of all the seven human coronaviruses M^pros. A detailed comparison of BFE components revealed that intermolecular van der Waals (vdW) interactions play a significantly more crucial role in maintaining association and determining the high binding affinity than intermolecular electrostatic interactions. Analyses of residue BFE decomposition reveals Cys145 as a pivotalt amino acid, positively influencing the stable binding between M^pros and inhibitor. These finding imply that PF-07321332 has the potential to be an effective anti-coronavirus inhibitor and also provide insights into inhibitor optimization and drug design strategies against human coronavirus.