Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
J Med Chem. 2010 Feb 25;53(4):1799-809. doi: 10.1021/jm901647p.
The recent progress in crystallography of G-protein coupled receptors opens an unprecedented venue for structure-based GPCR drug discovery. To test efficiency of the structure-based approach, we performed molecular docking and virtual ligand screening (VLS) of more than 4 million commercially available "drug-like" and ''lead-like'' compounds against the A(2A)AR 2.6 A resolution crystal structure. Out of 56 high ranking compounds tested in A(2A)AR binding assays, 23 showed affinities under 10 microM, 11 of those had sub-microM affinities and two compounds had affinities under 60 nM. The identified hits represent at least 9 different chemical scaffolds and are characterized by very high ligand efficiency (0.3-0.5 kcal/mol per heavy atom). Significant A(2A)AR antagonist activities were confirmed for 10 out of 13 ligands tested in functional assays. High success rate, novelty, and diversity of the chemical scaffolds and strong ligand efficiency of the A(2A)AR antagonists identified in this study suggest practical applicability of receptor-based VLS in GPCR drug discovery.
近年来，G 蛋白偶联受体的晶体学研究取得了突破性进展，为基于结构的 GPCR 药物发现开辟了前所未有的途径。为了测试基于结构的方法的效率，我们针对 A(2A)AR 的 2.6 A 分辨率晶体结构，对超过 400 万种商业上可用的“类药性”和“类先导化合物”进行了分子对接和虚拟配体筛选（VLS）。在 A(2A)AR 结合测定中测试的 56 种高排名化合物中，有 23 种化合物的亲和力低于 10 microM，其中 11 种化合物的亲和力低于亚微摩尔，有两种化合物的亲和力低于 60 nM。鉴定出的命中化合物代表至少 9 种不同的化学骨架，其配体效率非常高（每个重原子 0.3-0.5 千卡/摩尔）。在功能测定中，对 13 种测试配体中的 10 种进行了确认具有 A(2A)AR 拮抗剂活性。本研究中鉴定的 A(2A)AR 拮抗剂具有高成功率、新颖性、化学骨架多样性和强配体效率，表明基于受体的 VLS 在 GPCR 药物发现中具有实际应用价值。
