Identification of potential CCR5 inhibitors through pharmacophore-based virtual screening, molecular dynamics simulation and binding free energy analysis
Identification of potential CCR5 inhibitors through pharmacophore-based virtual screening, molecular dynamics simulation and binding free energy analysis
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通过基于药效团的虚拟筛选、分子动力学模拟和结合自由能分析鉴定潜在的 CCR5 抑制剂
DOI：
10.1039/c6mb00577b
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发表时间：
2016
影响因子：
--
通讯作者：
Lin Zhihua
中科院分区：
文献类型：
--
作者：
Wang Juan;Shu Mao;Wang Yuanqiang;Hu Yong;Wang Yuanliang;Luo Yanfeng;Lin Zhihua
CC趋化因子受体5（CCR5）是G蛋白偶联受体（GPCR）的一员，在感染的炎症反应中起着至关重要的作用。在许多类型的癌症中，CCR5表达的改变与疾病进展相关。使用CCR5作为治疗干预的靶点的想法已被证明可以预防疾病进展。迄今为止，只有少数化合物被报道为CCR 5抑制剂。本研究以一系列CCR5拮抗剂构建药效团模型。然后，最佳模型被用作一个三维查询，以确定新的化学实体的结构数据库。通过分子对接、药物相似性分析、分子动力学模拟（MDS）和结合自由能分析进行细化后，鉴定了三种潜在的抑制剂（25、29和45）。MD模拟表明，筛选的化合物保留了CCR5抑制剂（马拉韦罗和尼非韦罗）已知的重要共同结合模式，其占据了口袋的底部并稳定了CCR5的构象。在结合过程中，货车范德华力提供了实质性的驱动力。最有利的贡献来自Tyr37、Trp86、Tyr89、Tyr108、Phe109、Phe112、Gln194、Thr195、Ile198、Trp248、Tyr251、Leu255、Thr259、Met279、Glu283和Met287。上述结果表明，混合策略将提供一个合理的药物设计的基础。
CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), plays a vital role in inflammatory responses to infection. Alterations in the expression of CCR5 have been correlated with disease progression in many types of cancers. The idea of using CCR5 as a target for therapeutic intervention has been demonstrated to prevent disease progression. To date, only a few compounds have been reported as CCR5 inhibitors. In this study, a series of CCR5 antagonists were used to construct pharmacophore models. Then the optimal model was utilized as a 3D query to identify novel chemical entities from structural databases. After refinement by molecular docking, drug-likeness analysis, molecular dynamics simulations (MDS) and binding free energy analysis, three potential inhibitors (25, 29 and 45) were identified. MD simulations suggested that the screened compounds retained the important common binding mode known for CCR5 inhibitors (maraviroc and nifeviroc), which occupied the bottom of a pocket and stabilized the conformation of CCR5. During the binding process, van der Waals interactions provided the substantial driving force. The most favorable contributions were from Tyr37, Trp86, Tyr89, Tyr108, Phe109, Phe112, Gln194, Thr195, Ile198, Trp248, Tyr251, Leu255, Thr259, Met279, Glu283 and Met287. The above results suggest that the hybrid strategy would provide a basis for rational drug design.