Abstract

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.

Highlights

  • Glycolysis plays a central role in some tumor types

  • The binding region of these analogs is presumed to represent the catalytic site of Triosephosphate isomerase (TIM)

  • Structure-based virtual screening was used to identify an inhibitor of TIM

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Summary

Introduction

Many cancer cells are especially dependent on aerobic glycolysis for energy and metabolites. This dependence is known as the Warburg effect [1]. 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]

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