Inhibitors of Aspartate Transcarbamoylase Inhibit Mycobacterium tuberculosis Growth

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15640%2F23%3A73621865" target="_blank" >RIV/61989592:15640/23:73621865 - isvavai.cz</a>

Výsledek na webu

<a href="https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300279" target="_blank" >https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300279</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/cmdc.202300279" target="_blank" >10.1002/cmdc.202300279</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Inhibitors of Aspartate Transcarbamoylase Inhibit Mycobacterium tuberculosis Growth

Popis výsledku v původním jazyce

Aspartate transcarbamoylase (ATCase) plays a key role in the second step of de novo pyrimidine biosynthesis in eukaryotes and has been proposed to be a target to suppress cell proliferation in E. coli, human cells and the malarial parasite. We hypothesized that a library of ATCase inhibitors developed for malarial ATCase (PfATCase) may also contain inhibitors of the tubercular ATCase and provide a similar inhibition of cellular proliferation. Of the 70 compounds screened, 10 showed single-digit micromolar inhibition in an in vitro activity assay and were tested for their effect on M. tuberculosis cell growth in culture. The most promising compound demonstrated a MIC90 of 4 &amp; mu;M. A model of MtbATCase was generated using the experimental coordinates of PfATCase. In silico docking experiments showed this compound can occupy a similar allosteric pocket on MtbATCase to that seen on PfATCase, explaining the observed species selectivity seen for this compound series.

Název v anglickém jazyce

Inhibitors of Aspartate Transcarbamoylase Inhibit Mycobacterium tuberculosis Growth

Popis výsledku anglicky

Aspartate transcarbamoylase (ATCase) plays a key role in the second step of de novo pyrimidine biosynthesis in eukaryotes and has been proposed to be a target to suppress cell proliferation in E. coli, human cells and the malarial parasite. We hypothesized that a library of ATCase inhibitors developed for malarial ATCase (PfATCase) may also contain inhibitors of the tubercular ATCase and provide a similar inhibition of cellular proliferation. Of the 70 compounds screened, 10 showed single-digit micromolar inhibition in an in vitro activity assay and were tested for their effect on M. tuberculosis cell growth in culture. The most promising compound demonstrated a MIC90 of 4 &amp; mu;M. A model of MtbATCase was generated using the experimental coordinates of PfATCase. In silico docking experiments showed this compound can occupy a similar allosteric pocket on MtbATCase to that seen on PfATCase, explaining the observed species selectivity seen for this compound series.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

ChemMedChem

ISSN

1860-7179

e-ISSN

1860-7187

Svazek periodika

18

Číslo periodika v rámci svazku

17

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

7

Strana od-do

—

Kód UT WoS článku

001017616800001

EID výsledku v databázi Scopus

2-s2.0-85163771459