A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium
PBN-AR
Instytucja
Centrum Nowych Technologii UW (Uniwersytet Warszawski)
Informacje podstawowe
Główny język publikacji
en
Czasopismo
Computational Biology and Chemistry
ISSN
1476-9271
EISSN
Wydawca
ELSEVIER SCI LTD
DOI
URL
Rok publikacji
2015
Numer zeszytu
B
Strony od-do
91-97
Numer tomu
59
Liczba arkuszy
Autorzy
(liczba autorów: 4)
Pozostali autorzy
+ 3
Słowa kluczowe
en
Systems biology Metabolic modeling Homology modeling Drug repositioning Mycoplasma genitalium Thymidylate kinase
Streszczenia
Język
en
Treść
Abstract Bacteria are increasingly resistant to existing antibiotics, which target a narrow range of pathways. New methods are needed to identify targets, including repositioning targets among distantly related species. We developed a novel combination of systems and structural modeling and bioinformatics to reposition known antibiotics and targets to new species. We applied this approach to Mycoplasma genitalium, a common cause of urethritis. First, we used quantitative metabolic modeling to identify enzymes whose expression affects the cellular growth rate. Second, we searched the literature for inhibitors of homologs of the most fragile enzymes. Next, we used sequence alignment to assess that the binding site is shared by M. genitalium, but not by humans. Lastly, we used molecular docking to verify that the reported inhibitors preferentially interact with M. genitalium proteins over their human homologs. Thymidylate kinase was the top predicted target and piperidinylthymines were the top compounds. Further work is needed to experimentally validate piperidinylthymines. In summary, combined systems and structural modeling is a powerful tool for drug repositioning.
Cechy publikacji
ORIGINAL_ARTICLE
Inne
System-identifier
607450
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