title: Discovery of Mycobacterium tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.
abstract: 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.
authors.affiliation: National Institute of Chemistry , Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Tanja
authors.initials: T
authors.lastname: Štular
authors.affiliation: National Institute of Chemistry , Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Samo
authors.initials: S
authors.lastname: Lešnik
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Kaja
authors.initials: K
authors.lastname: Rožman
authors.affiliation: Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska , Glagoljaška 8, SI-6000 Koper, Slovenia.
authors.forename: Julia
authors.initials: J
authors.lastname: Schink
authors.affiliation: Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska , Glagoljaška 8, SI-6000 Koper, Slovenia.
authors.forename: Mitja
authors.initials: M
authors.lastname: Zdouc
authors.affiliation: Center for Molecular Modeling, Ghent University , Technologiepark 903, 9052 Zwijnaarde, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Ghysels
authors.affiliation: AAT Bioquest, Inc. , 520 Mercury Drive, Sunnyvale, California 94085, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , 308 Harvard Street Southeast, Minneapolis, Minnesota 55455, United States.
authors.forename: Courtney C
authors.identifier: 0000-0001-9261-594X
authors.initials: CC
authors.lastname: Aldrich
authors.affiliation: Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany.
authors.forename: V Joachim
authors.initials: VJ
authors.lastname: Haupt
authors.affiliation: Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany.
authors.forename: Sebastian
authors.identifier: 0000-0003-0662-2209
authors.initials: S
authors.lastname: Salentin
authors.affiliation: Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Daminelli
authors.affiliation: Biotechnology Center (BIOTEC), Technische Universität Dresden , 01307 Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schroeder
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna , Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.affiliation: Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska , Glagoljaška 8, SI-6000 Koper, Slovenia.
authors.forename: Dušanka
authors.initials: D
authors.lastname: Janežič
authors.affiliation: 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.
authors.forename: Janez
authors.initials: J
authors.lastname: Konc
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005227:Fatty Acids / Q000096:biosynthesis; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D005227:Fatty Acids; D008024:Ligands; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium