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<p>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<sup>pro</sup>) 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<sup>pro</sup>, 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<sup>pro</sup> utilizing covalent docking computations. Initially, the reliability of the AutoDock4.2.6 software in predicting M<sup>pro</sup>-ligand binding modes was validated based on accessible experimental data. Nirmatrelvir analogs with binding scores lower than nirmatrelvir (calc. −13.3&#xa0;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<i>G</i><sub>binding</sub> values of −49.7, −46.3, and −44.9&#xa0;kcal/mol, respectively, compared to nirmatrelvir (Δ<i>G</i><sub>binding</sub> = −40.7&#xa0;kcal/mol). The identified analogs demonstrated significant structural and energetic stability within M<sup>pro</sup> throughout 100 ns MDS. Evaluations of their drug-likeness and pharmacokinetic properties disclosed desirable oral bioavailability. The <i>in-silico</i> outcomes suggested that the identified analogs unveiled high potency as M<sup>pro</sup> inhibitors, highlighting the necessity for follow-up <i>in-vitro/in-vivo</i> evaluations to assess their efficacy as anti-COVID-19 agents.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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

摘要

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.