Scholarlink

<p>A myria d of drugs have entered clinical trials; however, due to the persistent limitations in drug discovery for SARS-CoV-2, the urgent need for novel therapeutic targets for COVID-19 persists. This study focuses on identifying novel antiviral inhibitors targeting the catalytic dyad and oxyanion-hole of main protease (Mpro) using integrated systems biology and dynamic undocking (DUck) approaches. From 105 N3-related analogs, ensemble docking identified three high-affinity ligands (<i>ΔG</i> ≤ -8.8&#xa0;kcal/mol). Molecular dynamics simulations revealed Mpro-ligand complex stability and highlighted structural disruptions in the catalytic dyad (His41-Cys145, <i>ΔD</i><sub><i>dyad</i></sub> &gt;1.0 Å) and oxyanion-hole loop (Gly143-Ser144-Cys145, <i>Δθ</i><sub><i>oxy</i></sub> &gt; 5°). DUck simulations elucidated a stepwise dissociation mechanism, identifying key hotspot residues (Phe140, His162, His164, Glu166, His172, Gln189, and Thr190) crucial for inhibitor binding. Among the screened compounds, CHEMBL5084942 and CHEMBL5086301 emerged as promising candidates, exhibiting robust interactions and slower dissociation rates (<i>W</i><sub>QB</sub> &gt;6&#xa0;kcal/mol). These ligands stabilized the receptor and induced conformational changes that may inhibit substrate binding. This block cluster mechanism of inhibition provides a robust framework for future inhibitor design. Moreover, favorable ADMET profiles further support their potential as drug candidates. This study lays a foundation for experimental validation and the development of effective antiviral therapies against SARS-CoV-2.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Discovery of novel inhibitor N3 scaffolds targeting the catalytic dyad and oxyanion-hole loop of SARS-CoV-2 Mpro: Insights from ensemble docking, molecular dynamics, dynamic undocking, and ADMET analysis

  • 期刊论文

  • 发表日期：

    2025年11月4日

查看全文
  • Kranthi Kumar Konidala,
  • Umadevi Bommu,
  • Suneetha Yeguvapalli

摘要

A myria d of drugs have entered clinical trials; however, due to the persistent limitations in drug discovery for SARS-CoV-2, the urgent need for novel therapeutic targets for COVID-19 persists. This study focuses on identifying novel antiviral inhibitors targeting the catalytic dyad and oxyanion-hole of main protease (Mpro) using integrated systems biology and dynamic undocking (DUck) approaches. From 105 N3-related analogs, ensemble docking identified three high-affinity ligands (ΔG ≤ -8.8 kcal/mol). Molecular dynamics simulations revealed Mpro-ligand complex stability and highlighted structural disruptions in the catalytic dyad (His41-Cys145, ΔDdyad >1.0 Å) and oxyanion-hole loop (Gly143-Ser144-Cys145, Δθoxy > 5°). DUck simulations elucidated a stepwise dissociation mechanism, identifying key hotspot residues (Phe140, His162, His164, Glu166, His172, Gln189, and Thr190) crucial for inhibitor binding. Among the screened compounds, CHEMBL5084942 and CHEMBL5086301 emerged as promising candidates, exhibiting robust interactions and slower dissociation rates (WQB >6 kcal/mol). These ligands stabilized the receptor and induced conformational changes that may inhibit substrate binding. This block cluster mechanism of inhibition provides a robust framework for future inhibitor design. Moreover, favorable ADMET profiles further support their potential as drug candidates. This study lays a foundation for experimental validation and the development of effective antiviral therapies against SARS-CoV-2.

Graphical Abstract