PF-07321332 is an orally active 3CL protease inhibitor, binding covalently and directly to the catalytic cysteine (Cys145) residue of the enzyme. It works as an anti-SARS-CoV-2 drug.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. The coronavirus 3-chymotrypsin-like protease (3CLpro) controls virus replication and is therefore considered a major target and promising opportunity for rational-based antiviral discovery with direct acting agents[1]. PF-07321332 is an oral antiviral SARS-CoV-2-3CL protease inhibitor[2]. The hydrogen bonds formed by lopinavir and ritonavir with 3CLpro are inconsistent and weak as compared with the interactions of 3CLpro with PF-07321332 and α-ketoamide. PF-07321332 showed more considerable binding energy toward 3CLpro, almost by 28 kJ/mol, and three times more than lopinavir and ritonavir. The interaction of PF-07321332 and α-ketoamide with the catalytic site residues may cause the distortion of the oxyanion hole in the reaction mechanism, and it may lead to the inhibition of 3CLpro in SARS-CoV-2. Compared with PF-07321332 and α-ketoamide, both antiretroviral drugs lopinavir and ritonavir manifested weaker interactions with 3CLpro, judging by binding energy values[3]. PF-07321332 was strongly bonded to 3CLpro and capable to disrupt the His41–Cys145 catalytic dyad, which, together with the N-terminus residues 1 to 7, is thought to have a vital role in proteolytic activity[4].
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