中国科学院上海药物研究所何欣恒小组的一项最新研究揭示，AlphaFold3与实验结构的更新：评估GPCR中小分子结合的精度。2025年7月9日出版的《中国药理学报》发表了这项成果。

在这项研究中，该课题组研究人员将74个AlphaFold3预测的结构与实验对应的结构进行了比较。该课题组人员发现，虽然AlphaFold3准确地捕获了全局受体结构和立构结合囊，这与他们之前的研究一致，但它的配体定位是高度可变的，往往是不准确的，使得预测不可靠，特别是对于变构调节剂。与实验结构的显著差异，特别是在复杂配体相互作用方面，突出了AlphaFold3的局限性，并强调了实验结构对于验证GPCR复合物中配体结合准确性仍然至关重要。

这些发现表明，虽然AlphaFold3为基于结构的药物设计提供了潜力，但其目前的不准确性需要大量的改进和与实验数据的整合。这项研究强调了AlphaFold3在预测小分子结合方面的局限性，并强调了高分辨率实验验证对可靠的GPCR-配体相互作用的关键作用。

据悉，G蛋白偶联受体（GPCR）是关键的药物发现靶点，其中许多是由小分子通过不同的结合机制调节的。AlphaFold3是一种领先的结构预测工具，可以对GPCR-小分子复合物进行建模，但其准确性尚未得到充分评估。

附：英文原文

Title: An update for AlphaFold3 versus experimental structures: assessing the precision of small molecule binding in GPCRs

Author: Shen, Shi-yi, Li, Jun-rui, Wang, Yu-song, Li, Shao-ning, Xu, H. Eric, He, Xin-heng

Issue&Volume: 2025-07-09

Abstract: G protein-coupled receptors (GPCRs) are key drug discovery targets with many of them modulated by small molecules via diverse binding mechanisms. AlphaFold3, a leading structure prediction tool, models GPCR-small molecule complexes, but its accuracy remains insufficiently evaluated. In this study we compared 74 AlphaFold3-predicted structures to experimental counterparts. We showed that while AlphaFold3 accurately captured global receptor architecture and orthosteric binding pockets, which was consistent with our previous research, its ligand positioning was highly variable and often inaccurate, rendering predictions unreliable, particularly for allosteric modulators. The significant divergence from experimental structures, particularly for complex ligand interactions, highlighted AlphaFold3’s limitations and underscored that experimental structures remained essential for validating ligand-binding accuracy in GPCR complexes. These findings suggest that while AlphaFold3 offers potential for structure-based drug design, its current inaccuracies necessitate substantial refinement and integration with experimental data. This study highlights the limitation of AlphaFold3 in predicting small molecule binding and reinforces the critical role of high-resolution experimental validation for reliable GPCR-ligand interactions.

DOI: 10.1038/s41401-025-01617-4

Source: https://www.nature.com/articles/s41401-025-01617-4