%0 Journal Article
%T A Novel Inhibitor of Mammalian Triosephosphate Isomerase Found by an In Silico Approach
%A Lorraine Marsh
%A Kaushal Shah
%J International Journal of Medicinal Chemistry
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/469125
%X 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. 1. Introduction Glycolysis plays a central role in some tumor types. Many cancer cells are especially dependent on aerobic glycolysis for energy and metabolites. This dependence is known as the Warburg effect [1]. Antiglycolytic drugs acting at various steps of the glycolysis pathway have shown potential to kill or impede tumors alone or in combination with classic drugs [2¨C4]. To date, no TIM inhibitors suitable for targeting mammalian TIM have been reported. The cell can control glucose metabolism to some extent via TP53 [5]. In a cellular process, TP53 signaling can inhibit the Warburg effect and shift tumor glycolysis flux, converting cells to a less transformed phenotype [6]. In part this normalization is due to a shift of glucose metabolism away from glycolysis and into oxidative phosphorylation and the pentose phosphate pathways [5, 6]. TIM is a key enzyme in glycolysis catalyzing the conversion of dihydroxyacetone phosphate to glyceraldehyde-3-phosphate [7]. TIM is an essential protein, and partial function mutations in hTPI1 are incompletely tolerated in humans [8]. Deficiency phenotypes for TIM are complicated by the accumulation of its substrate, dihydroxyacetone phosphate, which is
%U http://www.hindawi.com/journals/ijmc/2014/469125/