Investigation of the noncovalent binding mode of covalent proteasome inhibitors around the transition state by combined use of cyclopropylic strain-based conformational restriction and computational modeling

Shuhei Kawamura, Yuka Unno, Motohiro Tanaka, Takuma Sasaki, Akihito Yamano, Takatsugu Hirokawa, Tomoshi Kameda, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

To develop potent covalent inhibitors, the noncovalent interactions around the transition state to form covalent bonding should be optimized because the potency of the inhibitor can be depending on the energy of the transition state. Here, we report an efficient analysis of the noncovalent binding mode of a potent covalent proteasome inhibitor 3a around the transition state by a combined use of the chemical approach, i.e., the cyclopropylic strain-based conformational restriction, and the computational docking approach. Furthermore, we calculated the binding energy of a series of salinosporamide derivatives in the predicted noncovalent complex around the transition state with the simulation model of proteasome constructed in this study, which was well correlated to their pIC50. Thus, the proposed docking methods to predict the noncovalent binding mode around the transition state of covalent inhibitors will be helpful toward the development of covalent inhibitors.

Original languageEnglish
Pages (from-to)5829-5842
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number14
DOIs
Publication statusPublished - 2013 Jul 25

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