In target-based drug design,the manual creation of a poor initial compound library,the time-consuming wetlaboratory experimental screening method,and the weak explainability of their activity against compounds signifi...In target-based drug design,the manual creation of a poor initial compound library,the time-consuming wetlaboratory experimental screening method,and the weak explainability of their activity against compounds significantly limit the efficiency of discovering novel therapeutics.Here we propose an image-guided,interpretability deep learning workflow,named LeadDisFlow,to enable rapid,accurate target drug discovery.Using LeadDisFlow,we identified four potent antagonists with single-nanomolar antagonistic activity against PGE2 receptor subtype 4(EP4),a promising target for tumor im-munotherapy.Remarkably,the most potent EP4 antagonist,ZY001,demonstrated an IC50 value of(0.51±0.02)nM,along with high selectivity.Furthermore,ZY001 effectively impaired the PGE2-induced gene expression of a panel of immunosuppressive molecules in macrophages.The workflow facilitates the discovery of potent EP4 antagonists that enhance anti-tumor immune response,and provides a convenient and quick approach to discover promising therapeutics for a specific drug target.展开更多
基金supported by the National Natural Science Foundation of China (62425204, 62122025, U22A2037, 62450002,62432011, 62250028, 81972828, 82172644, and 81830083)Hunan Provincial Natural Science Foundation of China(2021JJ10020)+1 种基金National Key Scientific Infrastructure for Translational Medicine (Shanghai)(TMSK-2021-120)ECNU Multifunctional Platform for Innovation (011)
文摘In target-based drug design,the manual creation of a poor initial compound library,the time-consuming wetlaboratory experimental screening method,and the weak explainability of their activity against compounds significantly limit the efficiency of discovering novel therapeutics.Here we propose an image-guided,interpretability deep learning workflow,named LeadDisFlow,to enable rapid,accurate target drug discovery.Using LeadDisFlow,we identified four potent antagonists with single-nanomolar antagonistic activity against PGE2 receptor subtype 4(EP4),a promising target for tumor im-munotherapy.Remarkably,the most potent EP4 antagonist,ZY001,demonstrated an IC50 value of(0.51±0.02)nM,along with high selectivity.Furthermore,ZY001 effectively impaired the PGE2-induced gene expression of a panel of immunosuppressive molecules in macrophages.The workflow facilitates the discovery of potent EP4 antagonists that enhance anti-tumor immune response,and provides a convenient and quick approach to discover promising therapeutics for a specific drug target.
