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

文献类型：期刊论文

作者Shen, Shi-yi3,4,5; Li, Jun-rui4,5; Wang, Yu-song2; Li, Shao-ning1; Xu, H. Eric3,4,5; He, Xin-heng3,4,5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-07-09
页码10
关键词GPCR AlphaFold3 experimental structures global receptor architecture orthosteric binding pockets allosteric modulator structure-based drug design
ISSN号1671-4083
DOI10.1038/s41401-025-01617-4
英文摘要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.
WOS关键词DRUG DISCOVERY ; PERSPECTIVE ; IMPACT
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001527796900001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/318831]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Xu, H. Eric; He, Xin-heng
作者单位1.Chinese Univ Hong Kong, Dept Comp Sci & Engn, Hong Kong, Peoples R China
2.Xi An Jiao Tong Univ, Inst Artificial Intelligence & Robot, Xian 710049, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Shen, Shi-yi,Li, Jun-rui,Wang, Yu-song,et al. An update for AlphaFold3 versus experimental structures: assessing the precision of small molecule binding in GPCRs[J]. ACTA PHARMACOLOGICA SINICA,2025:10.
APA Shen, Shi-yi,Li, Jun-rui,Wang, Yu-song,Li, Shao-ning,Xu, H. Eric,&He, Xin-heng.(2025).An update for AlphaFold3 versus experimental structures: assessing the precision of small molecule binding in GPCRs.ACTA PHARMACOLOGICA SINICA,10.
MLA Shen, Shi-yi,et al."An update for AlphaFold3 versus experimental structures: assessing the precision of small molecule binding in GPCRs".ACTA PHARMACOLOGICA SINICA (2025):10.

入库方式： OAI收割

来源：上海药物研究所

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