Abstract
AbstractThe Janus kinase (JAK) family plays a pivotal role in most cytokine-mediated inflammatory and autoimmune responses via JAK/STAT signaling, and administration of JAK inhibitors is a promising therapeutic strategy for several diseases including COVID-19. However, to screen and design selective JAK inhibitors is a daunting task due to the extremely high homology among four JAK isoforms. In this study, we aimed to simultaneously predict pIC50 values of compounds for all JAK subtypes by constructing an interpretable GNN multitask regression model. The final model performance was positive, with R2 values of 0.96, 0.79 and 0.78 on the training, validation and test sets, respectively. Meanwhile, we calculated and visualized atom weights, followed by the rank sum tests and local mean comparisons to obtain key atoms and substructures that could be fine-tuned to design selective JAK inhibitors. Several successful case studies have demonstrated that our approach is feasible and our model could learn the interactions between proteins and small molecules well, which could provide practitioners with a novel way to discover and design JAK inhibitors with selectivity.
Graphical Abstract
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism
Publisher
Springer Science and Business Media LLC
Subject
Library and Information Sciences,Computer Graphics and Computer-Aided Design,Physical and Theoretical Chemistry,Computer Science Applications
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献