Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
The Evnin Family Laboratory of Computational Molecular Discovery, The Rockefeller University, New York, NY 10065, USA.
Science. 2024 Jun 21;384(6702):eadn6354. doi: 10.1126/science.adn6354.
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 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.
AlphaFold2 (AF2) 模型在回顾性配体识别方面产生了广泛的影响，但结果喜忧参半。我们前瞻性地将大型文库对接至未经精制的 σ 和血清素 2A（5-HT2A）受体的 AF2 模型，测试了数百种新分子，并将结果与对接实验结构的结果进行了比较。对于实验结构和 AF2 结构，对接的命中率都很高，亲和力也相似。尽管 AF2 模型中的变构残基构象与实验结构存在差异，但仍成功地对接至 AF2 模型。从 AF2 对接中确定的一种更有效的 5-HT2A 配体的低温电子显微镜结构表明，残基的适应类似于 AF2 的预测。AF2 模型可能会采样与实验结构不同的构象，但仍然保持低能量且与配体发现相关，从而扩展了基于结构的药物设计领域。
