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.

中文翻译：

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腺苷 G 蛋白偶联受体中变构调节剂的回顾性整体对接。

背景技术集成对接已被证明在药物发现和开发中是有用的。正如在包括 G 蛋白偶联受体 (GPCR) 在内的重要药物靶标上所证明的那样，它通过将受体灵活性纳入分子对接来提高命中率。腺苷 A1 受体 (A1AR) 是一种关键的 GPCR，已被靶向用于治疗心脏缺血再灌注损伤、神经性疼痛和肾脏疾病。变构调节剂的开发，与激动剂和拮抗剂相比，与不同且不太保守的 GPCR 靶位点结合的化合物，已经引起了人们对设计 A1AR 选择性药物的越来越多的兴趣。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 的分子对接的集成对接已用于 A1AR 中已知正变构调节剂 (PAM) 的回顾性对接。结果集成对接优于受体低温电磁结构的对接。计算的对接富集因子（EFs）和接收器操作特征曲线下面积（AUC）显着增加。结论 从 GaMD 模拟生成的受体集合能够提高发现 A1AR 的 PAM 的成功率。通过 GaMD 模拟和灵活对接来考虑受体灵活性非常重要。一般意义 集成对接是一种有前途的靶向柔性受体的药物发现方法。