Insights from integrated covalent docking and molecular dynamics simulations of nirmatrelvir analogs as potential SARS-CoV-2 Mpro inhibitors

The COVID-19 epidemic has posed a considerable challenge to the worldwide economy and public health, underscoring the crucial demand for developing effective antiviral medications. The SARS-CoV-2 main protease (M^pro) is a vital enzyme for antiviral drugs because of its fundamental function in viral reproduction. Nirmatrelvir (PF-07321332), a nitrile-based covalent ligand of M^pro, has garnered significant interest because it demonstrates additive efficacy when co-administered with ritonavir and is known as Paxlovid. Herein, forty-five nirmatrelvir analogs collected from the PubChem database were mined against M^pro utilizing covalent docking computations. Initially, the reliability of the AutoDock4.2.6 software in predicting M^pro-ligand binding modes was validated based on accessible experimental data. Nirmatrelvir analogs with binding scores lower than nirmatrelvir (calc. -13.3 kcal/mol) were advanced for molecular dynamics simulations (MDS), accompanied by binding energy assessments performed via the MM-GBSA approach. Based on MM-GBSA//100 ns MDS, PubChem-162-396-453, PubChem-162-396-449, and PubChem-162-396-448 exhibited superior binding affinities with ΔG_binding values of -49.7, -46.3, and -44.9 kcal/mol, respectively, compared to nirmatrelvir (ΔG_binding = -40.7 kcal/mol). The identified analogs demonstrated significant structural and energetic stability within M^pro throughout 100 ns MDS. Evaluations of their drug-likeness and pharmacokinetic properties disclosed desirable oral bioavailability. The in-silico outcomes suggested that the identified analogs unveiled high potency as M^pro inhibitors, highlighting the necessity for follow-up in-vitro/in-vivo evaluations to assess their efficacy as anti-COVID-19 agents.