Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells.

Details

Serval ID
serval:BIB_BEBF268FA936
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells.
Journal
Journal of Medicinal Chemistry
Author(s)
De Cesco S., Deslandes S., Therrien E., Levan D., Cueto M., Schmidt R., Cantin L.D., Mittermaier A., Juillerat-Jeanneret L., Moitessier N.
ISSN
1520-4804 (Electronic)
ISSN-L
0022-2623
Publication state
Published
Issued date
07/2012
Peer-reviewed
Oui
Volume
55
Number
14
Pages
6306-6315
Language
english
Notes
Publication types: Journal Article
Abstract
Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.
Pubmed
Web of science
Create date
31/07/2012 10:30
Last modification date
20/08/2019 15:33
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