title: Discovery of Novel Haloalkane Dehalogenase Inhibitors.
abstract: Haloalkane dehalogenases (HLDs) have recently been discovered in a number of bacteria, including symbionts and pathogens of both plants and humans. However, the biological roles of HLDs in these organisms are unclear. The development of efficient HLD inhibitors serving as molecular probes to explore their function would represent an important step toward a better understanding of these interesting enzymes. Here we report the identification of inhibitors for this enzyme family using two different approaches. The first builds on the structures of the enzymes' known substrates and led to the discovery of less potent nonspecific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of an HLD from the human pathogen Mycobacterium tuberculosis H37Rv. The best inhibitor exhibited high specificity for the target structure, with an inhibition constant of 3 μM and a molecular architecture that clearly differs from those of all known HLD substrates. The new inhibitors will be used to study the natural functions of HLDs in bacteria, to probe their mechanisms, and to achieve their stabilization.
authors.affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Buryska
authors.affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Daniel
authors.affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Antonin
authors.initials: A
authors.lastname: Kunka
authors.affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Brezovsky
authors.affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Damborsky
authors.affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic zbynek@chemi.muni.cz.|International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Prokop
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism*; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; D006867:Hydrolases; C046137:haloalkane dehalogenase