基于药效团模型筛选治疗新型冠状病毒肺炎DPP1抑制剂

Screening of DPP1 inhibitors as apotential treatment of COVID-19 based on pharmacophore

Cathepsin C(CTSC)基因是影响中国人群新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19)重症化的遗传易感基因之一,其编码的Dipeptidyl peptidase 1(DPP1)蛋白作为潜在的COVID-19治疗靶点,具有重要的临床意义。本文选取活性好且结构类似的DPP1小分子抑制剂组成训练集,利用Discovery Studio软件构建HipHop药效团。构建的药效团模型包含6个特征元素,包括3个氢键受体,2个芳香环中心和1个疏水中心。通过测试集和特征曲线图(ROC)验证,证实药效团模型具有较好的可靠性、稳定性和区分能力。使用该药效团模型筛选ZINC数据库中306347个小分子化合物,在依次进行类药性规则评判和分子对接研究,分析分子与蛋白的结合模式,选出3个潜在的DPP1抑制剂。预测上述小分子化合物的药物动力学性质(ADMET)和成药性,发现化合物7(ZINC12503660)最具成药优势,可以开发成治疗COVID-19的候选药物。同时,本文设计的多层次虚拟筛选方案也为设计和合成新的DPP1小分子抑制剂提供了参考。

Cathepsin C(CTSC)is one of the susceptibility genes that is significantly associated with the COVID-19 severity in Chinese population.The DPP1 is encoded by CTSC and has important clinical significance as a potential COVID-19 therapeutic target.In this paper,a HipHop pharmacophore was constructed by a training set composed ofthe DPP1 inhibitorswith better activity and similar structure by Discovery Studio.The pharmacophore model contained six characteristic elements:three hydrogen bondacceptors,two ring aromatics and one hydrophobic group.By passing the test set and ROC curve verification,the pharmacophore was verified with good reliability,stability and distinguishing ability.The 306347 molecules from the ZINC databasewere screened by the pharmacophore model,then followed by Lipinski and Veber rules judgement and molecular docking research,lastly,their interaction mode with DPP1 was analyzed.Three potential inhibitorsof DPP1 were selected.After prediction of ADMET and druggability,com-pound 7(ZINC12503660)was considered to be a potential treatment of COVID-19.Meanwhile,the strategy of multi-level virtual screening used in this paper provided a reference for the design and synthesis of new DPP1 inhibitors.