Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists.
Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists.
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DOI：
10.1021/jm901647p
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发表时间：
2010-02-25
影响因子：
7.3
通讯作者：
Abagyan R
中科院分区：
文献类型：
--
作者：
Katritch V;Jaakola VP;Lane JR;Lin J;Ijzerman AP;Yeager M;Kufareva I;Stevens RC;Abagyan R
g蛋白偶联受体晶体学的最新进展为基于结构的GPCR药物发现开辟了一个前所未有的场所。为了测试基于结构的方法的效率，我们针对A2AAR 2.6 Å分辨率晶体结构对超过400万种市售的“类药物”和“类铅”化合物进行了分子对接和虚拟配体筛选（VLS）。在56个A2AAR结合实验中，有23个化合物的亲和力低于10µM， 11个化合物的亲和力低于10µM， 2个化合物的亲和力低于60 nM。所鉴定的hit代表了至少9种不同的化学支架，并且具有非常高的配体效率（每个重原子0.3-0.5 kcal/mol）。在功能分析中，13个配体中有10个具有显著的A2AAR拮抗剂活性。本研究发现的A2AAR拮抗剂的高成功率、新颖性和多样性以及强配体效率表明基于受体的VLS在GPCR药物发现中的实用性。
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 A2AAR 2.6 Å resolution crystal structure. Out of 56 high ranking compounds tested in A2AAR binding assays, 23 showed affinities under 10 µM, eleven of those had sub-µM 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 A2AAR 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 A2AAR antagonists identified in this study suggest practical applicability of receptor-based VLS in GPCR drug discovery.
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影响因子：
7.3
作者：
DALY, JW
通讯作者：
DALY, JW
影响因子：
--
作者：
Fishman, P;Bar-Yehuda, S;Synowitz, M;Powell, J D;Klotz, K N;Gessi, S;Borea, P A
通讯作者：
Borea, P A
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M
影响因子：
--
作者：
Headrick, John P;Lasley, Robert D
通讯作者：
Lasley, Robert D
影响因子：
4
作者：
Brown, J;Brown, CA
通讯作者：
Brown, CA