Structural Basis of the Main Proteases of Coronavirus Bound to Drug Candidate PF-07321332

Abstract

The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA.

Structural Basis of Main Proteases of Coronavirus Bound to Drug Candidate PF-07304814

“…Recently, the crystal structures of GC376 and PF-07321332 in complex with SARS-CoV-2 M pro have been solved. 19 , 27 All of them form a C-S covalent bond with the catalytic cysteine and display a lactam ring at the P1 position ( Figure 4 ), which is suitable to occupy the S1 pocket by forming several hydrogen-bonding interactions with Phe140, His163, and Glu166. The binding pattern of PF-07304814 as well as PF-00835231 is similar to that of GC376 at the P2 position.…”

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

“…The trifluoromethyl group, instead, is important to anchor the inhibitor at the S4 subpocket by forming a stabilizing contact with Gln 192 and two ordered small molecules positioned in this site. 87 , 90 …”

“…The usual γ-lactamic ring fits into the S1 pocket and interacts with His 163 and Glu 166 , while the dimethyl-bicycloproline group is collocated into the hydrophobic S2 pocket and is surrounded by the side chains of His 41 , Met 49 , Tyr 54 , Met 165 , and Gln 189 , resulting in extensive van der Waals interactions. The trifluoromethyl group, instead, is important to anchor the inhibitor at the S4 subpocket by forming a stabilizing contact with Gln 192 and two ordered small molecules positioned in this site. , …”

“…The trifluoromethyl group, instead, is important to anchor the inhibitor at the S4 subpocket by forming a stabilizing contact with Gln 192 and two ordered small molecules positioned in this site. 87,90 Furthermore, given the importance of PF-07321332 as the first SARS-CoV-2 M PRO inhibitor approved for clinical use, a lot of advanced computational studies, such as steered molecular dynamics and classical-hybrid QM/MM simulations, have been conducted with the aim to clarify the mechanism of binding/ inhibition and thus to guide the design of new analogues. It has been demonstrated that P1 (γ-lactamic ring) and the P2 (dimethyl-cyclopropylproline group) are essential in the ligandbinding process, contributing positively to the total binding free energy (substitution with other groups determined a drastic reduction of binding affinity).…”

COVID-19 pandemic: A multidisciplinary perspective on the pathogenesis of a novel coronavirus from infection, immunity and pathological responses

“…In addition, studies have also identified inhibitors against novel coronavirus Mpro, including boceprevir, GC-376, and calpain inhibitors II and XII, which are often mimetic peptides that mimic natural peptide substrates and covalently bind to residue C145 in Mpro to exert inhibitory effects. (56). And a study selected 47 from the list of 3987 FDA-approved drugs for in vitro 3CLpro enzyme inhibitor screening test, and observed that boceprevir, ombitasvir, paritaprevir, tipranavir, and micafungin showed partial inhibition, and ivermectin blocked.…”