Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131, Padova, Italy.
School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK.
J Comput Aided Mol Des. 2018 Dec;32(12):1337-1346. doi: 10.1007/s10822-018-0174-2. Epub 2018 Oct 25.
The allosteric modulation of G protein-coupled receptors (GPCRs) by sodium ions has received considerable attention as crystal structures of several receptors, in their inactive conformation, show a Na ion bound to specific residues which, in the human A adenosine receptor (hA AR), are Ser91, Trp246, Asn280, and Asn284. A cluster of water molecules completes the coordination of the sodium ion in the putative allosteric site. It is absolutely consolidated that the progress made in the field of GPCRs structural determination has increased the adoption of docking-driven approaches for the identification or the optimization of novel potent and selective ligands. Despite the extensive use of docking protocols in virtual screening approaches, to date, almost any of these studies have been carried out without taking into account the presence of the sodium cation and its first solvation shell in the putative allosteric binding site. In this study, we have focused our attention on determining how the presence of sodium ion binding and additionally its first hydration sphere, in hAAR could influence the ligand positioning accuracy during molecular docking simulations for most of the available resting and activated hA AR crystal structures, using DockBench as a comparative benchmarking tool and implementing a new correlation coefficient (EM). This work provides indications on the evidence that the posing performance (accuracy and/or precision) of the docking protocols in reproducing the crystallographic poses of different hA AR antagonists is generally increased in the presence of the sodium cation and its first solvation shell, in agreement with experimental observations. Consequently, the inclusion of sodium ion and its first solvation shell should be considered in order to facilitate the selection of new potential ligands in all molecular docking-based virtual screening protocols that aim to find novel GPCRs antagonists and inverse agonists.
变构调节 G 蛋白偶联受体 (GPCRs) 的钠离子已收到相当多的关注，因为几个受体的晶体结构，在其非活性构象，显示一个 Na 离子绑定到特定的残基，在人类 A 腺苷受体 (hA AR)，是 Ser91，Trp246，Asn280 和 Asn284。一群水分子完成了钠离子在假定变构部位的配位。绝对可以肯定的是，在 GPCRs 结构测定领域取得的进展增加了对接驱动方法的应用，以鉴定或优化新型有效和选择性配体。尽管对接方案在虚拟筛选方法中得到了广泛的应用，但迄今为止，这些研究几乎都没有考虑到钠离子及其第一水合壳在假定变构结合位点中的存在。在这项研究中，我们专注于确定钠离子结合的存在，以及其第一水合壳在 hAAR 中的存在，如何影响配体在对接模拟中的定位精度，对于大多数可用的静息和激活 hAAR 晶体结构，使用 DockBench 作为比较基准工具，并实施新的相关系数 (EM)。这项工作提供了证据，表明在存在钠离子和其第一水合壳的情况下，对接方案在复制不同 hA AR 拮抗剂的晶体构象方面的定位性能（准确性和/或精度）普遍提高，这与实验观察结果一致。因此，为了促进在所有基于分子对接的虚拟筛选协议中选择新的潜在配体，以寻找新的 GPCRs 拮抗剂和反向激动剂，应考虑包含钠离子和其第一水合壳。
