靶向冠状病毒核衣壳蛋白NTD-RNA位点的小分子抑制剂虚拟筛选

Virtual Screening of Anti-Coronavirus Small Molecule Inhibitors Targeting NTD-RNA of Nucleocapsid Protein

摘要: 核衣壳蛋白(Nucleocapsid Protein，N蛋白)是冠状病毒(CoVs)家族保守的结构蛋白，其N端结构域(NTD)与病毒RNA结合形成核糖核蛋白复合物(RNP)，参与病毒复制与组装，已被认定为重要的抗冠状病毒药物靶点。以NTD-RNA结合位点为靶点，针对小分子片段库，开展基于计算机辅助药物设计方法的N蛋白抑制剂虚拟筛选。方法：建立基于受体结构的药效团模型，利用特征元素和测试集分子匹配程度选择最优模型，并运用基于受体和基于配体的方法以检验模型的可靠性。对小分子片段库进行基于Lipinski五规则、药效团模型和分子对接的虚拟筛选，筛选出可以干扰NTD与RNA结合的潜在N蛋白抑制剂。结果最佳药效团模型包含两个疏水特征和两个氢键受体，并筛选出药效团模型匹配值高、对接得分值排序靠前且结构新颖的2个化合物。结论：所筛选出的2个化合物可作为潜在的抑制剂以用于后续研究。

Abstract: Objective: The nucleocapsid protein (N protein) is a conserved structural protein of corona viruses (CoVs). The N-terminal domain (NTD) of N protein binds to viral RNA to form ribonucleoprotein complexes (RNPs), providing a site for virus replication and participating in particle assembly. Therefore, the N protein has been considered as an important antiviral target. Based on the small molecular fragment database, computer-aided drug design method was employed to screen potential N protein inhibitors targeting the interface of NTD-RNA. Methods: Pharmacophore models were constructed based on the reported structure of N protein and the optimal one was selected by the matching degree of the feature elements and test sets. The reliability of the model was further confirmed using receptor-based and ligand-based methods. Lipinski’s five rules, pharmacophore model and molecular docking-based virtual screening were performed to identify potential N protein inhibitors interrupting the interaction of NTD and RNA. Results: The best pharmacophore model contained two hydrophobic features and two hydrogen bond acceptors, and 2 compounds with high pharmacophore model fit values and docking scores were screened. Conclusion: The 2compounds will be further studied as potential inhibitors of N protein.