7YDX

Crystal structure of human RIPK1 kinase domain in complex with compound RI-962

7YDX の概要

• エントリーDOI: 10.2210/pdb7ydx/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 1, 1-methyl-5-[2-(2-methylpropanoylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-N-[(1S)-1-phenylethyl]indole-3-carboxamide, IODIDE ION, ... (4 entities in total)
• 機能のキーワード: ripk1, kinase, complex, inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68786.91

構造登録者

Zhang, L.,Wang, Y.,Li, Y.,Wu, C.,Luo, X.,Wang, T.,Lei, J.,Yang, S. (登録日: 2022-07-04, 公開日: 2023-04-19, 最終更新日: 2023-11-29)

主引用文献

Li, Y.,Zhang, L.,Wang, Y.,Zou, J.,Yang, R.,Luo, X.,Wu, C.,Yang, W.,Tian, C.,Xu, H.,Wang, F.,Yang, X.,Li, L.,Yang, S.
Generative deep learning enables the discovery of a potent and selective RIPK1 inhibitor.
Nat Commun, 13:6891-6891, 2022

PubMed 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.

PubMed: 36371441
DOI: 10.1038/s41467-022-34692-w

実験手法

X-RAY DIFFRACTION (2.642 Å)