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Background <p>The SARS-CoV-2 nsp10-nsp16 complex, a critical 2’-O-methyltransferase (MTase), plays a pivotal role in viral RNA capping, enabling immune evasion and efficient replication. </p> Methods <p>Our study employed a structure-based drug design (SBDD) approach to identify computationally prioritized candidates targeting the nsp10-nsp16 complex. Virtual screening of the ZINC20 In-Stock database using both AutoDock Vina and KarmaDock, one based on physics-driven scoring and the other on deep learning, identified six leading candidates with high affinity for the nsp16 active site.</p> Results <p>Among them, ZINC5222796, ZINC253388707, and ZINC100829855 showed the strongest binding affinities to the nsp16 active site. Among these, ZINC5222796, ZINC253388707, and ZINC100829855 demonstrated the highest binding affinities, with MM-GBSA binding free energies of -40.0 ± 0.09&#xa0;kcal/mol, -37.3 ± 0.07&#xa0;kcal/mol, and − 36.6 ± 0.09&#xa0;kcal/mol, respectively, surpassing the control compound tubercidin (-27.7 ± 0.10&#xa0;kcal/mol). Triplicate molecular dynamics (MD) simulations confirmed their robust stability, with low mean root mean square deviation (RMSD) and minimal structural fluctuations. These inhibitors exhibited extensive hydrogen bonding with critical active site residues, including ASP99, CYS115, and TYR132, contributing to their enhanced stability. Per-residue energy decomposition and DFT calculations further supported these findings, highlighting consistent interactions with key residues and favorable electronic properties that contribute to stable and high-affinity binding. The selected compounds demonstrated both stable binding and favorable energetics, surpassing the reference ligand in overall performance. </p> Conclusion <p>Collectively, these results indicate that the identified molecules stabilize key catalytic residues and maintain the conformational integrity of the active site throughout MD trajectories. Their favorable electronic profiles and sustained intermolecular contacts suggest potential to inhibit viral RNA capping by targeting the nsp10–nsp16 interface. This computational framework provides a foundation for rational optimization and experimental validation of nsp16-directed antiviral candidates.</p>

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Targeting the 2’-O-Methyltransferase Activity of SARS-CoV-2 nsp16 Through Discovery of Small Molecule Inhibitors Via an Integrated Computational Approach

  • 期刊论文

  • 发表日期：

    2025年11月22日

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  • Khulud Bukhari,
  • Rahmah Salem Alharbi,
  • Basmah F. Alharbi,
  • Wanian M Alwanian,
  • Hajed Obaid Alharbi,
  • Amal M. H. Mackawy,
  • Rana Alateeq,
  • Khaled S. Allemailem

摘要

Background

The SARS-CoV-2 nsp10-nsp16 complex, a critical 2’-O-methyltransferase (MTase), plays a pivotal role in viral RNA capping, enabling immune evasion and efficient replication.

Methods

Our study employed a structure-based drug design (SBDD) approach to identify computationally prioritized candidates targeting the nsp10-nsp16 complex. Virtual screening of the ZINC20 In-Stock database using both AutoDock Vina and KarmaDock, one based on physics-driven scoring and the other on deep learning, identified six leading candidates with high affinity for the nsp16 active site.

Results

Among them, ZINC5222796, ZINC253388707, and ZINC100829855 showed the strongest binding affinities to the nsp16 active site. Among these, ZINC5222796, ZINC253388707, and ZINC100829855 demonstrated the highest binding affinities, with MM-GBSA binding free energies of -40.0 ± 0.09 kcal/mol, -37.3 ± 0.07 kcal/mol, and − 36.6 ± 0.09 kcal/mol, respectively, surpassing the control compound tubercidin (-27.7 ± 0.10 kcal/mol). Triplicate molecular dynamics (MD) simulations confirmed their robust stability, with low mean root mean square deviation (RMSD) and minimal structural fluctuations. These inhibitors exhibited extensive hydrogen bonding with critical active site residues, including ASP99, CYS115, and TYR132, contributing to their enhanced stability. Per-residue energy decomposition and DFT calculations further supported these findings, highlighting consistent interactions with key residues and favorable electronic properties that contribute to stable and high-affinity binding. The selected compounds demonstrated both stable binding and favorable energetics, surpassing the reference ligand in overall performance.

Conclusion

Collectively, these results indicate that the identified molecules stabilize key catalytic residues and maintain the conformational integrity of the active site throughout MD trajectories. Their favorable electronic profiles and sustained intermolecular contacts suggest potential to inhibit viral RNA capping by targeting the nsp10–nsp16 interface. This computational framework provides a foundation for rational optimization and experimental validation of nsp16-directed antiviral candidates.