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Ligand efficacy reflects the ability to modulate receptor conformational states and extends beyond binding affinity to underpin functional selectivity. However, most computational approaches still emphasize affinity prediction, with limited capacity to capture the conformational dynamics driving efficacy. Here, we introduce Dynamic-GLEP, a structure- and mechanism-aware framework that integrates molecular dynamics (MD)\u2013derived conformational ensembles with transfer learning on equivariant graph neural networks. By constructing multi-conformation receptor\u2013ligand complexes and fine-tuning the EquiScore model, Dynamic-GLEP identifies conformation-dependent interaction features to distinguish agonists from nonagonists. Applied to the 5-HT1A receptor, the framework achieved an area under the curve (AUC) of 0.74 in cross-validation and 0.71 on an external Food and Drug Administration (FDA)-related dataset. Comparative analyses showed that Holo-based models are advantageous for scaffold optimization, whereas Apo-derived ensembles provided greater adaptability to chemically diverse ligands. Furthermore, extension to the adenosine A2A receptor yielded high performance (AUC\u2009&amp;gt;\u20090.85), underscoring the method\u2019s robustness and transferability under data-scarce conditions. Collectively, these results highlight Dynamic-GLEP as a reliable and interpretable platform for ligand efficacy prediction in Class A GPCRs, with broad potential to support virtual screening, candidate prioritization, and mechanism-driven drug design.<\/jats:p>","DOI":"10.1093\/bib\/bbag049","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T12:59:39Z","timestamp":1769086779000},"source":"Crossref","is-referenced-by-count":2,"title":["Dynamic-GLEP: a dynamics-informed deep learning framework for ligand efficacy prediction in representative Class A GPCRs"],"prefix":"10.1093","volume":"27","author":[{"given":"Zhiyi","family":"Chen","sequence":"first","affiliation":[{"name":"School of Life Sciences, Nanjing University , 163 Xianlin Avenue, Nanjing 210023 ,","place":["China"]},{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxin","family":"Hao","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203 ,","place":["China"]},{"name":"Division of Life Science and Medicine, University of Science and Technology of China , 443 Huangshan Road, Hefei\u00a0230026, Anhui ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Su","sequence":"additional","affiliation":[{"name":"Lingang Laboratory , 2380 Hechuan Road, Shanghai 200031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"\u00c5gren","sequence":"additional","affiliation":[{"name":"Division of X-ray Photon Science, Department of Physics and Astronomy, Uppsala University , Box 516, SE-751 20, Uppsala ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingan","family":"Chen","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203 ,","place":["China"]},{"name":"School of Physical Science and Technology, ShanghaiTech University , 393 Middle Huaxia Road, Shanghai 201210 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhehuan","family":"Fan","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0140-7998","authenticated-orcid":false,"given":"Duanhua","family":"Cao","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203 ,","place":["China"]},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou, Zhejiang 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiacheng","family":"Xiong","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203 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University, College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou, Zhejiang 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9547-0643","authenticated-orcid":false,"given":"Xutong","family":"Li","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3323-3092","authenticated-orcid":false,"given":"Mingyue","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Nanjing University , 163 Xianlin Avenue, Nanjing 210023 ,","place":["China"]},{"name":"Drug 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