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@article{1345850,
author = {Buryška, Tomáš and Daniel, Lukáš and Kunka, Antonín and Brezovský, Jan and Damborský, Jiří and Prokop, Zbyněk},
article_location = {WASHINGTON, DC (USA)},
article_number = {6},
doi = {http://dx.doi.org/10.1128/AEM.03916-15},
keywords = {SPHINGOMONAS-PAUCIMOBILIS UT26; AMBER FORCE-FIELD; MYCOBACTERIUM-TUBERCULOSIS; GENERALIZED BORN; SCORING FUNCTION; GAMMA-HEXACHLOROCYCLOHEXANE; BRADYRHIZOBIUM-JAPONICUM; CRYSTAL-STRUCTURE; PURIFICATION; SEQUENCE},
language = {eng},
issn = {0099-2240},
journal = {Applied and Environmental Microbiology},
title = {Discovery of Novel Haloalkane Dehalogenase Inhibitors},
url = {https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/},
volume = {82},
year = {2016}
}
TY - JOUR
ID - 1345850
AU - Buryška, Tomáš - Daniel, Lukáš - Kunka, Antonín - Brezovský, Jan - Damborský, Jiří - Prokop, Zbyněk
PY - 2016
TI - Discovery of Novel Haloalkane Dehalogenase Inhibitors
JF - Applied and Environmental Microbiology
VL - 82
IS - 6
SP - 1958-1965
EP - 1958-1965
PB - AMER SOC MICROBIOLOGY
SN - 00992240
KW - SPHINGOMONAS-PAUCIMOBILIS UT26
KW - AMBER FORCE-FIELD
KW - MYCOBACTERIUM-TUBERCULOSIS
KW - GENERALIZED BORN
KW - SCORING FUNCTION
KW - GAMMA-HEXACHLOROCYCLOHEXANE
KW - BRADYRHIZOBIUM-JAPONICUM
KW - CRYSTAL-STRUCTURE
KW - PURIFICATION
KW - SEQUENCE
UR - https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/
L2 - https://loschmidt.chemi.muni.cz/peg/publications/discovery-of-novel-haloalkane-dehalogenase-inhibitors/
N2 - 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.
ER -
BURYŠKA, Tomáš, Lukáš DANIEL, Antonín KUNKA, Jan BREZOVSKÝ, Jiří DAMBORSKÝ a Zbyněk PROKOP. Discovery of Novel Haloalkane Dehalogenase Inhibitors. \textit{Applied and Environmental Microbiology}. WASHINGTON, DC (USA): AMER SOC MICROBIOLOGY, roč.~82, č.~6, s.~1958-1965. ISSN~0099-2240. doi:10.1128/AEM.03916-15. 2016.
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