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

Author's Department

Chemistry Department

Fifth Author's Department

Chemistry Department

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https://doi.org/10.1038/s41598-025-24162-w

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Mahmoud A.A. Ibrahim Doaa M.A. Khaled Doaa G.M. Mahmoud Alaa H.M. Abdelrahman Tamer Shoeib Peter A. Sidhom Yanshuo Han Badr Aldahmash Ahmed Rady

Document Type

Research Article

Publication Title

Scientific Reports

Publication Date

12-1-2025

doi

10.1038/s41598-025-24162-w

Abstract

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 (Mpro) is a vital enzyme for antiviral drugs because of its fundamental function in viral reproduction. Nirmatrelvir (PF-07321332), a nitrile-based covalent ligand of Mpro, 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 Mpro utilizing covalent docking computations. Initially, the reliability of the AutoDock4.2.6 software in predicting Mpro-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 ΔGbinding values of −49.7, −46.3, and −44.9 kcal/mol, respectively, compared to nirmatrelvir (ΔGbinding = −40.7 kcal/mol). The identified analogs demonstrated significant structural and energetic stability within Mpro 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 Mpro inhibitors, highlighting the necessity for follow-up in-vitro/in-vivo evaluations to assess their efficacy as anti-COVID-19 agents.

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