Clarissa G. Jakob, Anup K. Upadhyay, Pamela L. Donner, Emily Nicholl, Sadiya N. Addo, Wei Qiu, Christopher Ling, Sujatha M. Gopalakrishnan, Maricel Torrent, Steven P. Cepa, Jason Shanley, Alexander R. Shoemaker, Chaohong C. Sun∥, Anil Vasudevan, Kevin R. Woller, J. Brad Shotwell, Bailin Shaw, Zhiguo Bian, and Jessica E. Hutti
J. Med. Chem, 2018 61 (15), 6647–6657
IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive α,β-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter and @firstname.lastname@example.org on Mastodon
Thursday, August 9, 2018
Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315
Covalent drug discovery using sulfur(VI) fluoride exchange warheads
Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 https://doi.org/10.1080/17460441.2023.2218642 Covalent drug discovery has ...
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Wang, S.; Hadisurya, M.; Tao, W. A.; Dykhuizen, E.; Krusemark, C. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-tvgn1 Targeted co...
Jian Ding, Guo Li, Hejun Liu, Lulu Liu, Ying Lin, Jingyan Gao, Guoqiang Zhou, Lingling Shen, Mengxi Zhao, Yanyan Yu, Weihui Guo, Ulrich Homm...