Discovery of Novel Haloalkane Dehalogenase Inhibitors

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Publikace nespadá pod Pedagogickou fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.
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BURYŠKA Tomáš DANIEL Lukáš KUNKA Antonín BREZOVSKÝ Jan DAMBORSKÝ Jiří PROKOP Zbyněk

Rok publikování 2016
Druh Článek v odborném periodiku
Časopis / Zdroj Applied and Environmental Microbiology
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/
Doi http://dx.doi.org/10.1128/AEM.03916-15
Obor Biochemie
Klíčová slova SPHINGOMONAS-PAUCIMOBILIS UT26; AMBER FORCE-FIELD; MYCOBACTERIUM-TUBERCULOSIS; GENERALIZED BORN; SCORING FUNCTION; GAMMA-HEXACHLOROCYCLOHEXANE; BRADYRHIZOBIUM-JAPONICUM; CRYSTAL-STRUCTURE; PURIFICATION; SEQUENCE
Popis 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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