抗肿瘤新靶点MTH1抑制剂药效团模型的研究

Study on Pharmacophore Model of Novel Anti-Tumor Target MTH1 Inhibitors

目的:研究抗肿瘤靶点人MutT同源体1蛋白(Human MutT Homolog-1,MTH1)抑制剂的构效关系,构建药效团筛选模型筛选潜在的MTH1抑制剂。方法:采用计算机辅助药物设计方法,通过Discovery Studio 3.0软件包中分子共同特征药效团HipHop算法,使用14个已知MTH1抑制剂分子作为训练集构建药效团模型,并通过Decoy Set验证准确性。结果:获得富集率为13.1的HipHop药效团模型,通过分子对接验证虚拟筛选出的75个候选化合物,得到先导化合物GK01945和HTS07767,能与受体形成良好的相互作用。结论:构建的药效团模型可以作为筛选模型,筛选出的MTH1潜在抑制剂,为抗肿瘤药物MTH1抑制剂开发提供了新思路。

Objective To investigate the quantitative structure-activity relationship of anti-tumor target Human MutT Homolog-1 protein(MTH1)inhibitors,develop pharmacophore screening model to screen potential MTH1 inhibitors.Methods Using computer-aided drug design method,HipHop algorithm in Discovery Studio 3.0 software packages were used to build pharmacophore model using 14 known MTH1 inhibitor molecules as training Set,and the accuracy was evaluated by Decoy Set.Results The pharmacophore model with enrichment rate of 13.1 was obtained,and the candidate compounds GK01945 and HTS07767 were verified by molecular docking to form a good interaction with the receptor.Conclusion The pharmacophore model constructed can be used as a screening model to screen out potential inhibitors of MTH1,providing a new idea for the development of anti-tumor drug MTH1 inhibitors.