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<p>Chikungunya virus poses a significant public health risk due to the absence of specific antiviral treatments. It causes serious symptoms, such as polyarthralgia, high fever, muscle pain, nausea, and rash. nsP2 is a non-structural protein of CHIKV that has been extensively studied because of its multifunctional nature and role as a protease in the viral life cycle. Inhibiting this enzyme could prevent viral replication, making it a desirable target for developing new antiviral drugs. This study employed a rational, literature-guided <i>in silico</i> approach to design and evaluate 25 benzimidazole derivatives as potential CHIKV nsP2 protease inhibitors, built upon two experimentally validated parent scaffolds, MBZM-N-IBT and oxibendazole. Molecular docking was performed using AutoDock 4.2.6 in a two-stage workflow: whole-protein docking of all 25 compounds, followed by focused active-site docking of top-ranked candidates. Drug likeness and toxicological profiling were performed using SwissADME and ProTox 3.0, respectively. Four compounds, 2f, 2h, 2e, and 2g, were identified with predicted binding free energies ranging from − 8.27 to − 7.95&#xa0;kcal/mol, exceeding both reference inhibitors. Focused docking confirmed that compounds 2g and 2f bind directly within the catalytic cleft, forming hydrogen bonds with Cys1013 at 3.38 Å and 3.28 Å, respectively. Compound 2g demonstrated the strongest pose convergence of 72%, while compound 2f showed the most consistent binding predictions. All compounds satisfied Lipinski’s Rule of Five, and both lead compounds were assigned to GHS Toxicity Class V as they had LD<sub>50</sub> values ≥ 2700&#xa0;mg/kg. Compound 2g was identified as the primary lead, and compound 2f as a strong secondary lead for further experimental validation as CHIKV nsP2 protease inhibitors.</p>

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Exploring benzimidazole derivatives as potential inhibitors of chikungunya virus protease using in silico methods

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Jeffrey E. Sampson,
  • Chandan Nakum,
  • Joseph Muganga,
  • Julius Mashaga

摘要

Chikungunya virus poses a significant public health risk due to the absence of specific antiviral treatments. It causes serious symptoms, such as polyarthralgia, high fever, muscle pain, nausea, and rash. nsP2 is a non-structural protein of CHIKV that has been extensively studied because of its multifunctional nature and role as a protease in the viral life cycle. Inhibiting this enzyme could prevent viral replication, making it a desirable target for developing new antiviral drugs. This study employed a rational, literature-guided in silico approach to design and evaluate 25 benzimidazole derivatives as potential CHIKV nsP2 protease inhibitors, built upon two experimentally validated parent scaffolds, MBZM-N-IBT and oxibendazole. Molecular docking was performed using AutoDock 4.2.6 in a two-stage workflow: whole-protein docking of all 25 compounds, followed by focused active-site docking of top-ranked candidates. Drug likeness and toxicological profiling were performed using SwissADME and ProTox 3.0, respectively. Four compounds, 2f, 2h, 2e, and 2g, were identified with predicted binding free energies ranging from − 8.27 to − 7.95 kcal/mol, exceeding both reference inhibitors. Focused docking confirmed that compounds 2g and 2f bind directly within the catalytic cleft, forming hydrogen bonds with Cys1013 at 3.38 Å and 3.28 Å, respectively. Compound 2g demonstrated the strongest pose convergence of 72%, while compound 2f showed the most consistent binding predictions. All compounds satisfied Lipinski’s Rule of Five, and both lead compounds were assigned to GHS Toxicity Class V as they had LD50 values ≥ 2700 mg/kg. Compound 2g was identified as the primary lead, and compound 2f as a strong secondary lead for further experimental validation as CHIKV nsP2 protease inhibitors.