Computing the relative binding affinity of ligands based on a pairwise binding comparison network

Author:

Yu Jie,Li Zhaojun,Chen Geng,Kong Xiangtai,Hu Jie,Wang Dingyan,Cao Duanhua,Li Yanbei,Huo Ruifeng,Wang Gang,Liu Xiaohong,Jiang Hualiang,Li XutongORCID,Luo XiaominORCID,Zheng MingyueORCID

Abstract

AbstractStructure-based lead optimization is an open challenge in drug discovery, which is still largely driven by hypotheses and depends on the experience of medicinal chemists. Here we propose a pairwise binding comparison network (PBCNet) based on a physics-informed graph attention mechanism, specifically tailored for ranking the relative binding affinity among congeneric ligands. Benchmarking on two held-out sets (provided by Schrödinger and Merck) containing over 460 ligands and 16 targets, PBCNet demonstrated substantial advantages in terms of both prediction accuracy and computational efficiency. Equipped with a fine-tuning operation, the performance of PBCNet reaches that of Schrödinger’s FEP+, which is much more computationally intensive and requires substantial expert intervention. A further simulation-based experiment showed that active learning-optimized PBCNet may accelerate lead optimization campaigns by 473%. Finally, for the convenience of users, a web service for PBCNet is established to facilitate complex relative binding affinity prediction through an easy-to-operate graphical interface.

Publisher

Springer Science and Business Media LLC

Subject

Computer Networks and Communications,Computer Science Applications,Computer Science (miscellaneous)

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