Discovery of FIXa inhibitors by combination of pharmacophore modeling, molecular docking, and 3D-QSAR modeling
Discovery of FIXa inhibitors by combination of pharmacophore modeling, molecular docking, and 3D-QSAR modeling
复制标题
通过结合药效团建模、分子对接和 3D-QSAR 建模发现 FIXa 抑制剂
DOI：
10.1080/10799893.2018.1468784
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发表时间：
2018-01-01
影响因子：
2.8
通讯作者：
Zuo, ZhiLi
中科院分区：
文献类型：
--
作者：
Li, Penghua;Peng, Jiale;Zuo, ZhiLi
摘要人凝血因子IXa（FIXa）在凝血级联反应的起始阶段被特异性抑制，是开发选择性和安全性抗凝剂的良好靶点。为了探索这种抑制机制，选择86个FIXa抑制剂来生成药效团模型和随后的SAR模型。通过受体-配体药效团生成模块建立最佳药效团模型和ROC曲线。建立了基于分子对接和PLS因子分析的CoMFA模型。模型传播值为q2 = 0.709、r2 = 0.949和r2 pred = 0.905。CoMSIA的q2值为0.609，r2值为0.962，r2 pred值为0.819，表明CoMFA和CoMSIA模型均可用于预测对FIXa的抑制活性。在药效团建模、分子对接和3D-QSAR模型筛选的基础上，筛选出6个具有潜在FIXa抑制剂活性的分子。
Abstract Human Coagulation Factor IXa (FIXa), specifically inhibited at the initiation stage of the blood coagulation cascade, is an excellent target for developing selective and safe anticoagulants. To explore this inhibitory mechanism, 86 FIXa inhibitors were selected to generate pharmacophore models and subsequently SAR models. Both best pharmacophore model and ROC curve were built through the Receptor–Ligand Pharmacophore Generation module. CoMFA model based on molecular docking and PLS factor analysis methods were developed. Model propagations values are q2 = 0.709, r2 = 0.949, and r2pred = 0.905. The satisfactory q2 value of 0.609, r2 value of 0.962, and r2pred value of 0.819 for CoMSIA indicated that the CoMFA and CoMSIA models are both available to predict the inhibitory activity on FIXa. On the basis of pharmacophore modeling, molecular docking, and 3D-QSAR modeling screening, six molecules are screened as potential FIXa inhibitors.