The continued global tuberculosis epidemic has motivated drug design targeting specific enzymatic processes of the infectious bacterium, Mycobacterium tuberculosis. One such process within the tricarboxylic acid (TCA) cycle, the glyoxylate shunt, has garnered particular interest. The glyoxylate shunt bypasses two traditional CO2-generating steps in the TCA cycle by incorporating a molecule of acetyl-coenzyme A as the carbon source, therefore propagating the TCA cycle under carbon limiting conditions during chronic infection. Of the two enzymes involved in the glyoxylate shunt, malate synthase was targeted for structure-based drug design by the Sacchettini lab for its large, conformationally static active site1. Inhibition was observed for phenyl-diketo acid and various phenyl-substituted derivatives. Upon inhibition, the diketo acid backbone binds to the catalytic Mg2+ ion and participates in hydrogen-bonding interactions with nearby residues while the terminal aryl group participates in an anion-π interaction with an aspartate residue. Previous computational studies by another group identified the importance of long range electrostatic interactions during inhibition2. In collaboration with the Wheeler and Sacchettini labs, we are further exploring the energetic underpinnings of the interactions involved in enzymatic inhibition for thirteen inhibitors, including the electrostatic interactions with the Mg2+ ion, the series of hydrogen bonding interactions along the backbone, and the anion-π interaction present at the aryl moiety. From the series of inhibited protein crystal structures, the appropriate model active site is extracted and analyzed computationally using a DFT method well established in handling non-covalent interactions (M06-2X/6-31G+(d)). Analysis of the anion-π interaction in response to substitution on the aryl moiety is pursued to develop an efficient screening method for the determination of new, potent inhibitors for further drug development targeting the glyoxylate shunt in Mycobacterium tuberculosis. Krieger, I. V. et al. Chemistry & Biology, 2012, 19, 1556–1567. Estarellas, C. et al. ChemPhysChem, 2013, 14, 145-154.

Computational exploration of the noncovalent interactions involved in the inhibition of malate synthase for treatment of tuberculosis

249th National Meeting (2015)

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