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Targeting the cryptic sites: NMR-based strategy to improve protein druggability.
Summary: In collaboration with RIKEN, Daiichi-sankyo RD NOVARE,AMED, and Technology Research Association for Next generation natural products chemistry, the research group of Koh Takeuchi and Yuji Tokunaga (Dynamic Pharmaco-modality Research Group) developed, a novel NMR based strategy to identify and stabilize the lowly populated open cryptic site conformation by NMR dynamics information, and semi-rationally designed allosteric mutations. The utilization of the mutant substantially enhanced the efficiency to identify a ligand that bind to the target protein. These results clearly indicate that protein druggability can be improved by analyzing and controlling the dynamics of proteins, which would represent a versatile and complement strategy for PPI inhibitor development. The details are discussed in Science Advances (doi: 10.1126/sciadv.abd0480), which is published in Sep, 30, 2020.
Strength of NMR to identify lowly populated conformational state enables us to identify and improve the druggability of cryptic sites.
Reference
Title：Targeting the cryptic sites: NMR-based strategy to improve protein druggability by controlling the conformational equilibrium.
Authors： Y. Mizukoshi*, K. Takeuchi*†, Y. Tokunaga, H. Matsuo, M. Imai, M. Fujisaki, H. Kamoshida, T. Takizawa, H. Hanzawa, I. Shimada†(*: equal contribution, †: corresponding authors)
Journal： Science Advances, Sep, 30 (2020)