title: 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.
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.
authors.affiliation: Faculty of Pharmaceutical Sciences and ‡Center for Research and Education on Drug Discovery, Hokkaido University , Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kawamura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Unno
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tanaka
authors.forename: Takuma
authors.initials: T
authors.lastname: Sasaki
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamano
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Kameda
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D061988:Proteasome Inhibitors