The retrieval of hit/lead compounds with novel scaffolds during early drug development is an important but challenging task. Various generative models have been proposed to create drug-like molecules. However, the capacity of these generative models to design wet-lab-validated and target-specific molecules with novel scaffolds has hardly been verified. We herein propose a generative deep learning (GDL) model, a distribution-learning conditional recurrent neural network (cRNN), to generate tailor-made virtual compound libraries for given biological targets. The GDL model is then applied to RIPK1. Virtual screening against the generated tailor-made compound library and subsequent bioactivity evaluation lead to the discovery of a potent and selective RIPK1 inhibitor with a previously unreported scaffold, RI-962. This compound displays potent in vitro activity in protecting cells from necroptosis, and good in vivo efficacy in two inflammatory models. Collectively, the findings prove the capacity of our GDL model in generating hit/lead compounds with unreported scaffolds, highlighting a great potential of deep learning in drug discovery.
Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.
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