BACKGROUND:Ensemble docking has proven useful in drug discovery and development. It increases the hit rate by incorporating receptor flexibility into molecular docking as demonstrated on important drug targets including G-protein-coupled receptors (GPCRs). Adenosine A1 receptor (A1AR) is a key GPCR that has been targeted for treating cardiac ischemia-reperfusion injuries, neuropathic pain and renal diseases. Development of allosteric modulators, compounds binding to distinct and less conserved GPCR target sites compared with agonists and antagonists, has attracted increasing interest for designing selective drugs of the A1AR. Despite significant advances, more effective approaches are needed to discover potent and selective allosteric modulators of the A1AR. METHODS:Ensemble docking that integrates Gaussian accelerated molecular dynamic (GaMD) simulations and molecular docking using Autodock has been implemented for retrospective docking of known positive allosteric modulators (PAMs) in the A1AR. RESULTS:Ensemble docking outperforms docking of the receptor cryo-EM structure. The calculated docking enrichment factors (EFs) and the area under the receiver operating characteristic curves (AUC) are significantly increased. CONCLUSIONS:Receptor ensembles generated from GaMD simulations are able to increase the success rate of discovering PAMs of A1AR. It is important to account for receptor flexibility through GaMD simulations and flexible docking. GENERAL SIGNIFICANCE:Ensemble docking is a promising approach for drug discovery targeting flexible receptors.

译文

背景:集成对接已被证明在药物发现和开发中很有用。如重要药物靶标(包括G蛋白偶联受体(GPCR))所示,它通过将受体的柔韧性结合到分子对接中来提高命中率。腺苷A1受体(A1AR)是关键的GPCR,已被靶向治疗心脏缺血-再灌注损伤,神经性疼痛和肾脏疾病。与激动剂和拮抗剂相比,变构调节剂(与不同且不那么保守的GPCR靶位点结合的化合物)的开发吸引了越来越多的兴趣来设计A1AR选择性药物。尽管取得了重大进展,但仍需要更有效的方法来发现A1AR的有效和选择性变构调节剂。
方法:集成了高斯加速分子动力学(GaMD)模拟和使用Autodock进行分子对接的集成对接已实现了对A1AR中已知的正构构调节剂(PAM)的追溯对接。
结果:整体对接优于对接体cryo-EM结构的对接。计算出的对接富集因子(EFs)和接收器工作特性曲线(AUC)下的面积显着增加。
结论:GaMD模拟产生的受体集合能够提高发现A1AR PAM的成功率。重要的是要通过GaMD模拟和灵活的对接考虑受体的灵活性。
一般意义:整合对接是一种针对靶向柔性受体的药物发现的有前途的方法。

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