dvancing Ligand Binding Affinity Prediction with Cartesian Tensor-Based Deep Learning
We present PBCNet2.0, a cartesian tensor-based Siamese Neural Network for protein-ligand relative binding affinity prediction. Trained on 8.6 milion protein-ligand complex structure pairs, PBCNet2.0 achieves zero-shot performance comparable to computationally intensive physics-based simulations. Our prioritization experiments show that PBCNet2.0 speeds up binding affinity optimization by 718% while reducing resource use by 41%. Through extensive retrospective experiments, we demonstrate that PBCNet2.0 intrinsically comprehends protein-ligand interactions, showing high sensitivity to intermolecular interactions and exceptional perception of spatial geometric information. Strikingly, PBCNet2.0 exhibits an emergent capability to predict affinity changes induced by binding residue variations, highlighting its potential for identifying resistance mutation. We prospectively validated these capabilities on two targets ENPpl and ALDH1Bl, where PBCNet2.0 successfully identified affinity shifts arising from subtle molecular interactions and conformational differences, and pinpointed critical binding residues with an 83% hit rate. This combination of computational efficiency, spatial geometric perception of binding site, and generalizable affinity prediction establishes PBCNet2.0 as a transformative tool for developing pharmacological probes for all human proteins.
Ma, Huicong、ao, Tian、Rao, Jingxin、hen, Mingan、hen, Kaixian、Li, Xutong、eng, Dan、Luo, Xiaomin、Wang, Mingliang、Zhang, Sulin、Zheng, Mingyue、Zhang, Yingying、Shao, Panpan、Yu, Jie、Sheng, Xia、Fan, Zhehuan、Wang, Zhaokun、ao, Duanhua、Hao, Yongxin
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400, China;School of Pharmacy, Zunyi Medical University, Zunyi, 563000, ChinaZhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400, China;State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550014, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaSchool of Physical Science and Technology, Shanghai Tech University, Shanghai, 201210, China;Lingang Laboratory, Shanghai 200031, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaZhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400, China;Department of Medicinal Chemistry，Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zu Chong Zhi Road, Shanghai 201203, China;School of Pharmacy, Zunyi Medical University, Zunyi, 563000, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;School of Information Science and Technology, Shanghai Tech University, Shanghai, 201210, China;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, ChinaDivision of Life Science and Medicine, University of Science and Technology of China, Hefei, 230026, Anhui, China;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, ChinaLingang Laboratory, Shanghai 200031, China;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, China;School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaSchool of Information Science and Technology, Shanghai Tech University, Shanghai, 201210, China;Lingang Laboratory, Shanghai 200031, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;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, ChinaSchool of Life Sciences and Technology, Tongji University, Shanghai, 200092, ChinaDivision of Life Science and Medicine, University of Science and Technology of China, Hefei, 230026, Anhui, China;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, China
生物化学分子生物学计算技术、计算机技术
PBCNet2.0Siamese Neural NetworkLigand Binding Affinity Predictioneep Learning
PBCNet2.0Siamese Neural NetworkLigand Binding Affinity Predictioneep Learning
Ma, Huicong,ao, Tian,Rao, Jingxin,hen, Mingan,hen, Kaixian,Li, Xutong,eng, Dan,Luo, Xiaomin,Wang, Mingliang,Zhang, Sulin,Zheng, Mingyue,Zhang, Yingying,Shao, Panpan,Yu, Jie,Sheng, Xia,Fan, Zhehuan,Wang, Zhaokun,ao, Duanhua,Hao, Yongxin.dvancing Ligand Binding Affinity Prediction with Cartesian Tensor-Based Deep Learning[EB/OL].(2025-07-29)[2025-08-03].https://chinaxiv.org/abs/202507.00458.点此复制
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