A Novel Inhibitor of Mammalian Triosephosphate Isomerase Found by an In Silico Approach
Joint Authors
Source
International Journal of Medicinal Chemistry
Issue
Vol. 2014, Issue 2014 (31 Dec. 2014), pp.1-6, 6 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2014-03-23
Country of Publication
Egypt
No. of Pages
6
Main Subjects
Abstract EN
Triosephosphate isomerase (TIM) is an essential, highly conserved component of glycolysis.
Tumors are often dependent on glycolysis for energy and metabolite production (the Warburg effect).
Glycolysis inhibitors thus show promise as cancer treatments.
TIM inhibition, unlike inhibition of other glycolysis enzymes, also produces toxic methylglyoxal targeted to regions of high glycolysis, an effect that might also be therapeutically useful.
Thus TIM is an attractive drug target.
A total of 338,562 lead-like molecules were analyzed computationally to find TIM inhibitors by an efficient “double screen” approach.
The first fragment-sized compounds were studied using structure-based virtual screening to identify binding motifs for mammalian TIM.
Subsequently, larger compounds, filtered to meet the binding criteria developed in the first analysis, were ranked using a second round of structure-based virtual screening.
A compound was found that inhibited mammalian TIM in vitro in the micromolar range.
Docking and molecular dynamics (MD) suggested that the inhibitor made hydrogen bond contacts with TIM catalytic residues.
In addition, hydrophobic contacts were made throughout the binding site.
All predicted inhibitor-TIM interactions involved TIM residues that were highly conserved.
The discovered compound may provide a scaffold for elaboration of other inhibitors.
American Psychological Association (APA)
Marsh, Lorraine& Shah, Kaushal. 2014. A Novel Inhibitor of Mammalian Triosephosphate Isomerase Found by an In Silico Approach. International Journal of Medicinal Chemistry،Vol. 2014, no. 2014, pp.1-6.
https://search.emarefa.net/detail/BIM-473950
Modern Language Association (MLA)
Marsh, Lorraine& Shah, Kaushal. A Novel Inhibitor of Mammalian Triosephosphate Isomerase Found by an In Silico Approach. International Journal of Medicinal Chemistry No. 2014 (2014), pp.1-6.
https://search.emarefa.net/detail/BIM-473950
American Medical Association (AMA)
Marsh, Lorraine& Shah, Kaushal. A Novel Inhibitor of Mammalian Triosephosphate Isomerase Found by an In Silico Approach. International Journal of Medicinal Chemistry. 2014. Vol. 2014, no. 2014, pp.1-6.
https://search.emarefa.net/detail/BIM-473950
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-473950