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1.  Structure-based Ligand Design and the Promise Held for Antiprotozoan Drug Discovery* 
The Journal of Biological Chemistry  2009;284(18):11749-11753.
The development of the pharmaceutical industry, driven by progress in chemistry, biology, and technology, ranks as one of the most successful of human endeavors. However, serious health problems persist, among which are diseases caused by protozoan parasites, largely ignored in modern times. Advances in genomic sciences, molecular and structural biology, and computational and medicinal chemistry now set the scene for a renewed assault on such infections. A structure-centric approach to support discovery of antiparasitic compounds promises much. Current strategies and benefits of a structure-based approach to support early stage drug discovery will be described.
doi:10.1074/jbc.R800072200
PMCID: PMC2673241  PMID: 19103598
2.  Leishmania Trypanothione Synthetase-Amidase Structure Reveals a Basis for Regulation of Conflicting Synthetic and Hydrolytic Activities*S⃞ 
The Journal of Biological Chemistry  2008;283(25):17672-17680.
The bifunctional trypanothione synthetase-amidase catalyzes biosynthesis and hydrolysis of the glutathione-spermidine adduct trypanothione, the principal intracellular thiol-redox metabolite in parasitic trypanosomatids. These parasites are unique with regard to their reliance on trypanothione to determine intracellular thiol-redox balance in defense against oxidative and chemical stress and to regulate polyamine levels. Enzymes involved in trypanothione biosynthesis provide essential biological activities, and those absent from humans or for which orthologues are sufficiently distinct are attractive targets to underpin anti-parasitic drug discovery. The structure of Leishmania major trypanothione synthetase-amidase, determined in three crystal forms, reveals two catalytic domains. The N-terminal domain, a cysteine, histidine-dependent amidohydrolase/peptidase amidase, is a papain-like cysteine protease, and the C-terminal synthetase domain displays an ATP-grasp family fold common to C:N ligases. Modeling of substrates into each active site provides insight into the specificity and reactivity of this unusual enzyme, which is able to catalyze four reactions. The domain orientation is distinct from that observed in a related bacterial glutathionylspermidine synthetase. In trypanothione synthetase-amidase, the interactions formed by the C terminus, binding in and restricting access to the amidase active site, suggest that the balance of ligation and hydrolytic activity is directly influenced by the alignment of the domains with respect to each other and implicate conformational changes with amidase activity. The potential inhibitory role of the C terminus provides a mechanism to control relative levels of the critical metabolites, trypanothione, glutathionylspermidine, and spermidine in Leishmania.
doi:10.1074/jbc.M801850200
PMCID: PMC2427367  PMID: 18420578

Results 1-2 (2)