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International Journal of Medicinal Chemistry
Volume 2014, Article ID 469125, 6 pages
Research Article

A Novel Inhibitor of Mammalian Triosephosphate Isomerase Found by an In Silico Approach

Department of Biology, Long Island University, 1 University Plaza, Brooklyn, NY 11201, USA

Received 6 November 2013; Revised 18 December 2013; Accepted 7 January 2014; Published 23 March 2014

Academic Editor: Giulio Rastelli

Copyright © 2014 Lorraine Marsh and Kaushal Shah. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.