Discovery of Mycobacterium tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.

Autor: Štular T; National Institute of Chemistry , Hajdrihova 19, SI-1000 Ljubljana, Slovenia., Lešnik S; National Institute of Chemistry , Hajdrihova 19, SI-1000 Ljubljana, Slovenia., Rožman K; Faculty of Pharmacy, University of Ljubljana , Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia., Schink J; Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska , Glagoljaška 8, SI-6000 Koper, Slovenia., Zdouc M; Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska , Glagoljaška 8, SI-6000 Koper, Slovenia., Ghysels A; Center for Molecular Modeling, Ghent University , Technologiepark 903, 9052 Zwijnaarde, Belgium., Liu F; AAT Bioquest, Inc. , 520 Mercury Drive, Sunnyvale, California 94085, United States., Aldrich CC; Department of Medicinal Chemistry, University of Minnesota , 308 Harvard Street Southeast, Minneapolis, Minnesota 55455, United States., Haupt VJ; Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany., Salentin S; Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany., Daminelli S; Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany., Schroeder M; Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany., Langer T; Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna , Althanstrasse 14, A-1090 Vienna, Austria., Gobec S; Faculty of Pharmacy, University of Ljubljana , Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia., Janežič D; Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska , Glagoljaška 8, SI-6000 Koper, Slovenia., Konc J; National Institute of Chemistry , Hajdrihova 19, SI-1000 Ljubljana, Slovenia.; Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska , Glagoljaška 8, SI-6000 Koper, Slovenia.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2016 Dec 22; Vol. 59 (24), pp. 11069-11078. Date of Electronic Publication: 2016 Dec 12.
DOI: 10.1021/acs.jmedchem.6b01277
Abstrakt: Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiS-ligands approach, which for a given protein structure allows prediction of its binding sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins. The plugin enables advanced viewing of predicted binding sites, ligands' poses, and their interactions in three-dimensional graphics. Using the InhA query protein, an enoyl reductase enzyme in the Mycobacterium tuberculosis fatty acid biosynthesis pathway, we predicted its possible ligands and assessed their inhibitory activity experimentally. This resulted in three previously unrecognized inhibitors with novel scaffolds, demonstrating the plugin's utility in the early drug discovery process.
Databáze: MEDLINE
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