Abstract
Although several constitutive proteasome inhibitors have been reported these recent years, potent organic, noncovalent and readily available inhibitors are still poorly documented. Here we used a structure- and ligand-based in silico approach to identify commercially available 1,2,4-oxadiazole derivatives as non-covalent human 20S proteasome inhibitors. Their optimization led to the newly synthesized compound 4h that is a mixed proteasomal inhibitor of the chymotrypsin- like activity (Ki of 26,1 nM and K’i of 7.5 nM) which is in addition selective versus the challenging cathepsin B and calpain proteases. Molecular modelling studies corroborated the mechanism of inhibition and suggest an unusual binding of the inhibitor within the S5 binding pocket (β6 subunit). The cellular effects of our compounds validate their utility as potential pharmacological agents for anti-cancer pre-clinical studies.
Keywords: Chymotrypsin-like subsite S5 binding, cytotoxicity, non-covalent inhibitors, oxadiazoles, proteasome, virtual screening.
Current Medicinal Chemistry
Title:1,2,4-Oxadiazoles Identified by Virtual Screening and their Non-Covalent Inhibition of the Human 20S Proteasome
Volume: 20 Issue: 18
Author(s): X. Maréchal, E. Genin, L. Qin, O. Sperandio, M. Montes, N. Basse, N. Richy, M.A. Miteva, M. Reboud-Ravaux, J. Vidal and B.O. Villoutreix
Affiliation:
Keywords: Chymotrypsin-like subsite S5 binding, cytotoxicity, non-covalent inhibitors, oxadiazoles, proteasome, virtual screening.
Abstract: Although several constitutive proteasome inhibitors have been reported these recent years, potent organic, noncovalent and readily available inhibitors are still poorly documented. Here we used a structure- and ligand-based in silico approach to identify commercially available 1,2,4-oxadiazole derivatives as non-covalent human 20S proteasome inhibitors. Their optimization led to the newly synthesized compound 4h that is a mixed proteasomal inhibitor of the chymotrypsin- like activity (Ki of 26,1 nM and K’i of 7.5 nM) which is in addition selective versus the challenging cathepsin B and calpain proteases. Molecular modelling studies corroborated the mechanism of inhibition and suggest an unusual binding of the inhibitor within the S5 binding pocket (β6 subunit). The cellular effects of our compounds validate their utility as potential pharmacological agents for anti-cancer pre-clinical studies.
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Maréchal X., Genin E., Qin L., Sperandio O., Montes M., Basse N., Richy N., Miteva M.A., Reboud-Ravaux M., Vidal J. and Villoutreix B.O., 1,2,4-Oxadiazoles Identified by Virtual Screening and their Non-Covalent Inhibition of the Human 20S Proteasome, Current Medicinal Chemistry 2013; 20 (18) . https://dx.doi.org/10.2174/0929867311320180006
DOI https://dx.doi.org/10.2174/0929867311320180006 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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