Insights from integrated covalent docking and molecular dynamics simulations of nirmatrelvir analogs as potential SARS-CoV-2 Mpro inhibitors
Mahmoud A. A. Ibrahim, Doaa M. A. Khaled, Doaa G. M. Mahmoud, Alaa H. M. Abdelrahman, Peter A. Sidhom, Yanshuo Han, Tamer Shoeib, Badr Abdullah Aldahmash, Ahmed Moustafa Rady · Scientific Reports · 2025
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 Δ G binding values of −49.7, −46.3, and −44.9 kcal/mol, respectively, compared to nirmatrelvir (Δ G 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.