Department of Chemistry, University of York , Heslington, York, YO10 5DD, U.K.
Departament de Quı́mica Inorgànica i Orgànica (Secció de Química Orgànica) & Institut de Quimica Teòrica i Computacional (IQTCUB), Universitat de Barcelona , Martí i Franquès 1, 08028 Barcelona, Spain.
J Am Chem Soc. 2017 May 17;139(19):6534-6537. doi: 10.1021/jacs.7b01773. Epub 2017 May 5.
The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine-both covalent retaining β-glucosidase inhibitors-we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the H transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the H conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (K = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the H conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.
糖基水解酶的构象分析为通过过渡态模拟来实现其特异性抑制提供了一条途径。受环磷醇和环磷醇氮杂环丙烷（均为共价保留β-葡萄糖苷酶抑制剂）的快速反应速率的启发，我们推测相应的碳杂“环丙基”类似物将是通过 H 过渡态构象反应的那些酶的有效保留β-葡萄糖苷酶抑制剂。环丙基抑制剂构象自由能景观的从头算分子动力学模拟显示出对 H 构象的强烈偏向，并且具有 N-(4-叠氮丁基)羧酰胺部分的碳杂-环磷醇确实是一种有效的抑制剂（K = 8.2 nM） Thermotoga maritima TmGH1 β-葡萄糖苷酶。3-D 结构分析和与未反应的环氧化物的比较表明，该化合物确实以 H 构象结合，这表明通过环丙基单元诱导的构象应变可能会增加紧密结合抑制剂设计的武器库。
