Discovery of Novel Haloalkane Dehalogenase Inhibitors

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Authors

BURYŠKA Tomáš DANIEL Lukáš KUNKA Antonín BREZOVSKÝ Jan DAMBORSKÝ Jiří PROKOP Zbyněk

Year of publication 2016
Type Article in Periodical
Magazine / Source Applied and Environmental Microbiology
MU Faculty or unit

Faculty of Science

Citation
Web https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/
Doi http://dx.doi.org/10.1128/AEM.03916-15
Field Biochemistry
Keywords SPHINGOMONAS-PAUCIMOBILIS UT26; AMBER FORCE-FIELD; MYCOBACTERIUM-TUBERCULOSIS; GENERALIZED BORN; SCORING FUNCTION; GAMMA-HEXACHLOROCYCLOHEXANE; BRADYRHIZOBIUM-JAPONICUM; CRYSTAL-STRUCTURE; PURIFICATION; SEQUENCE
Description 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 mu M 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.
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