Discovery of novel haloalkane dehalogenase inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F16%3A00064013" target="_blank" >RIV/00159816:_____/16:00064013 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14310/16:00087944

Výsledek na webu

<a href="http://dx.doi.org/10.1128/AEM.03916-15" target="_blank" >http://dx.doi.org/10.1128/AEM.03916-15</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1128/AEM.03916-15" target="_blank" >10.1128/AEM.03916-15</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of novel haloalkane dehalogenase inhibitors

Popis výsledku v původním jazyce

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 towards 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 non-specific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of a 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.

Název v anglickém jazyce

Discovery of novel haloalkane dehalogenase inhibitors

Popis výsledku anglicky

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 towards 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 non-specific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of a 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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EE - Mikrobiologie, virologie

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Applied and Environmental Microbiology

ISSN

0099-2240

e-ISSN

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Svazek periodika

82

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

8

Strana od-do

1958-1965

Kód UT WoS článku

000373339400032

EID výsledku v databázi Scopus

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