期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 121, 期 -, 页码 578-591出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.05.049
关键词
Proteasome inhibitors; Non-covalent; Peptide scaffold; Docking studies; Virtual screening
资金
- Ministero dell'Istruzione, dell'Universita e della Ricerca Scientifica e Tecnologica [MIUR-PRIN], Rome, Italy [2010W7YRLZ_003, 2010W7YRLZ_004]
- Research & Mobility Program of the University of Messina
Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors, e.g. carfilzomib, used in cancer therapy. A multistep hierarchical structure-based virtual screening (SBVS) of the 65,375 NCI lead-like compound library led to the identification of two compounds (9 and 28) which noncovalently inhibited the chymotrypsin-like (ChT-L) activity (K-i = 2.18 and 2.12 mu M, respectively) with little or no effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and post-glutamyl peptide hydrolase (PGPH) activities. A subsequent hierarchical similarity search over the full NCI database with the most active tripeptide-based inhibitor 9 resulted in the discovery of the beta 5/beta 6-specific tripeptide derivative 38 that noncovalently binds the ChT-L site (K-i = 0.42 mu M). The solution structure of 9 and 38 was solved by H-1 NMR spectroscopy and the binding mode of the inhibitors was elucidated by docking experiments using the yeast 20S proteasome. Compound 38 (IC50 = 26.7 mu M) is slightly more potent than 9 (IC50 = 34.3 mu M) at inhibiting survival of dexamethasone-resistant (MM.1R) human multiple myeloma cells. The identified ligand thus provides valuable insights for the future structure-based design of subtype-specific proteasome inhibitors. (C) 2016 Elsevier Masson SAS. All rights reserved.
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