对接(动物)
亲缘关系
化学
计算生物学
立体化学
配体(生物化学)
氨基酸残基
受体
生物物理学
生物
生物化学
肽序列
医学
护理部
基因
作者
Jiankun Lyu,Nicholas J. Kapolka,Ryan H. Gumpper,Assaf Alon,Liang Wang,Manish K. Jain,Ximena Barros-Álvarez,Kensuke Sakamoto,Yoojoong Kim,Jeffrey F. DiBerto,Kuglae Kim,Isabella Glenn,Tia A. Tummino,Sijie Huang,John J. Irwin,Olga O. Tarkhanova,Yurii S. Moroz,Georgios Skiniotis,Andrew C. Kruse,Brian K. Shoichet,Bryan L. Roth
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2024-06-21
卷期号:384 (6702)
被引量:2
标识
DOI:10.1126/science.adn6354
摘要
AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ 2 and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo–electron microscopy structure for one of the more potent 5-HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based drug design.
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