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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)

Doi: 10.1126/sciadv.abd0480

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