G蛋白偶联受体
同源建模
对接(动物)
药物发现
计算生物学
受体
配体(生物化学)
化学
立体化学
晶体结构
生物
生物信息学
结晶学
生物化学
酶
医学
护理部
作者
Jens Carlsson,Ryan G. Coleman,Vincent Setola,John J. Irwin,Hao Fan,Avner Schlessinger,Andrej Šali,Bryan L. Roth,Brian K. Shoichet
摘要
A virtual screen of the GPCR D3R based on a homology model prior to publication of the crystal structure and a subsequent virtual screen based on the crystal structure of the receptor once it became available both identified new ligands with verified activities. G protein–coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling. With the determination of the first crystal structures, interest in structure-based ligand discovery increased. Unfortunately, for most GPCRs no experimental structures are available. The determination of the D3 receptor structure and the challenge to the community to predict it enabled a fully prospective comparison of ligand discovery from a modeled structure versus that of the subsequently released crystal structure. Over 3.3 million molecules were docked against a homology model, and 26 of the highest ranking were tested for binding. Six had affinities ranging from 0.2 to 3.1 μM. Subsequently, the crystal structure was released and the docking screen repeated. Of the 25 compounds selected, five had affinities ranging from 0.3 to 3.0 μM. One of the new ligands from the homology model screen was optimized for affinity to 81 nM. The feasibility of docking screens against modeled GPCRs more generally is considered.
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