Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
Curr Pharm Des. 2019;25(7):783-816. doi: 10.2174/1381612825666190304123414.
Adenosine receptors (ARs) are transmembrane proteins that belong to the G protein-coupled receptors (GPCRs) superfamily and mediate the biological functions of adenosine. To date, four AR subtypes are known, namely A1, A2A, A2B and A3 that exhibit different signaling pathways, tissue localization, and mechanisms of activation. Moreover, the widespread ARs and their implication in numerous physiological and pathophysiological conditions had made them pivotal therapeutic targets for developing clinically effective agents. The crystallographic success in identifying the 3D crystal structures of A2A and A1 ARs has dramatically enriched our understanding of their structural and functional properties such as ligand binding and signal transduction. This, in turn, has provided a structural basis for a larger contribution of computational methods, particularly molecular dynamics (MD) simulations, toward further investigation of their molecular properties and designing bioactive ligands with therapeutic potential. MD simulation has been proved to be an invaluable tool in investigating ARs and providing answers to some critical questions. For example, MD has been applied in studying ARs in terms of ligand-receptor interactions, molecular recognition, allosteric modulations, dimerization, and mechanisms of activation, collectively aiding in the design of subtype selective ligands. In this review, we focused on the advances and different applications of MD simulations utilized to study the structural and functional aspects of ARs that can foster the structure-based design of drug candidates. In addition, relevant literature was briefly discussed which establishes a starting point for future advances in the field of drug discovery to this pivotal group of drug targets.
腺苷受体（ARs）是一种跨膜蛋白，属于 G 蛋白偶联受体（GPCRs）超家族，介导腺苷的生物学功能。迄今为止，已知有四种 AR 亚型，即 A1、A2A、A2B 和 A3，它们表现出不同的信号通路、组织定位和激活机制。此外，广泛存在的 ARs 及其在众多生理和病理生理条件中的作用，使它们成为开发临床有效药物的重要治疗靶点。在确定 A2A 和 A1 AR 三维晶体结构方面的晶体学成功，极大地丰富了我们对其结构和功能特性的理解，如配体结合和信号转导。这反过来又为计算方法，特别是分子动力学（MD）模拟，提供了更大的贡献，以进一步研究其分子特性和设计具有治疗潜力的生物活性配体提供了结构基础。MD 模拟已被证明是研究 ARs 并为一些关键问题提供答案的宝贵工具。例如，MD 已被应用于研究 ARs 中的配体-受体相互作用、分子识别、变构调节、二聚化和激活机制，共同有助于设计亚型选择性配体。在这篇综述中，我们重点介绍了 MD 模拟在研究 ARs 的结构和功能方面的应用进展和不同应用，这有助于基于结构的候选药物设计。此外，还简要讨论了相关文献，为这一关键药物靶点领域的药物发现未来进展奠定了基础。
