Drug design and repurposing with a sequence-to-drug paradigm
Chen, L.; Fan, Z.; Chang, J.; Yang, R.; Guo, H.; Zhang, Y.; Yang, T.; Zhou, C.; Chen, Z.; Zheng, C.; Hao, X.; Zhang, K.; Cui, R.; Ding, Y.; Zhang, N.; Luo, X.; Jiang, H.; Zhang, S.; Zheng, M.
Show abstract
Drug development based on target proteins has been a successful approach in recent decades. A conventional structure-based drug design pipeline is a complex, human-engineered pipeline with multiple independently optimized steps. Advances in end-to-end differentiable learning suggest the potential benefits of similarly reformulating drug design. Here, we proposed a new sequence-to-drug paradigm that discovers drug-like small-molecule modulators directly from protein sequences and validated this concept for the first time in three stages. First, we designed TransformerCPI2.0 as a core tool for the sequence-to-drug paradigm, which exhibited competitive performance with conventional structure-based drug design approaches. Second, we validated the binding knowledge that TransformerCPI2.0 has learned. Third, we applied a sequence-to-drug paradigm to discover new hits for E3 ubiquitin-protein ligases: speckle-type POZ protein (SPOP), ring finger protein 130 (RNF130) which does not have a 3D structure, and repurposed proton pump inhibitors (PPIs) for ADP-ribosylation factor 1 (ARF1). This first proof of concept shows that the sequence-to-drug paradigm is a promising direction for drug development.
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