Generative deep learning enables the discovery of a potent and selective RIPK1 inhibitor

Yueshan Li, Liting Zhang, Yifei Wang, Jun Zou, Ruicheng Yang, Xinling Luo, Chengyong Wu, Wei Yang, Chenyu Tian, Haixing Xu, Falu Wang, Xin Yang, Linli Li and Shengyong Yang ()
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Yueshan Li: Sichuan University
Liting Zhang: Sichuan University
Yifei Wang: Sichuan University
Jun Zou: Sichuan University
Ruicheng Yang: Sichuan University
Xinling Luo: Sichuan University
Chengyong Wu: Sichuan University
Wei Yang: Sichuan University
Chenyu Tian: Sichuan University
Haixing Xu: Sichuan University
Falu Wang: Sichuan University
Xin Yang: Sichuan University
Linli Li: Sichuan University
Shengyong Yang: Sichuan University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34692-w

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