Faculty of Pharmacy, Department of Pharmaceutical Chemistry, King Salman International University (KSIU), Ras Sudr, Egypt.
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Kafrelsheikh University, Kafrelsheikh, Egypt.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):563-572. doi: 10.1080/14756366.2021.2022659.
On account of its crucial role in the virus life cycle, SARS-COV-2 NSP13 helicase enzyme was exploited as a promising target to identify a novel potential inhibitor using multi-stage structure-based drug discovery approaches. Firstly, a 3D pharmacophore was generated based on the collected data from a protein-ligand interaction fingerprint (PLIF) study using key interactions between co-crystallised fragments and the NSP13 helicase active site. The ZINC database was screened through the generated 3D-pharmacophore retrieving 13 potential hits. All the retrieved hits exceeded the benchmark score of the co-crystallised fragments at the molecular docking step and the best five-hit compounds were selected for further analysis. Finally, a combination between molecular dynamics simulations and MM-PBSA based binding free energy calculations was conducted on the best hit (compound ) bound to NSP13 helicase enzyme, which identified as a potential potent NSP13 helicase inhibitor with binding free energy equals -328.6 ± 9.2 kcal/mol.
由于其在病毒生命周期中的关键作用，SARS-CoV-2 NSP13 解旋酶被用作一个有前途的靶点，通过多阶段基于结构的药物发现方法来识别一种新的潜在抑制剂。首先，基于使用共结晶片段和 NSP13 解旋酶活性位点之间的关键相互作用的蛋白质-配体相互作用指纹（PLIF）研究中收集的数据，生成了一个 3D 药效团。通过生成的 3D 药效团筛选 ZINC 数据库，检索到 13 个潜在的命中物。在分子对接步骤中，所有检索到的命中物都超过了共结晶片段的基准分数，并且选择了最佳的 5 个命中物化合物进行进一步分析。最后，对与 NSP13 解旋酶酶结合的最佳命中物（化合物 ）进行分子动力学模拟和基于 MM-PBSA 的结合自由能计算的组合，鉴定出 作为一种具有结合自由能为-328.6±9.2 kcal/mol 的潜在 NSP13 解旋酶抑制剂。
