Dihydrofolate reductase: A potential drug target in trypanosomes and leishmania |
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Authors: | Fabio Zuccotto Andrew C.R Martin Roman A. Laskowski Janet M. Thornton Ian H. Gilbert |
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Affiliation: | (1) University of Wales Cardiff, King Edward VII Avenue, Cardiff, CF1 3XF, U.K;(2) Department of Biochemistry and Molecular Biology, Biomolecular Structure and Modelling Unit, University College London, Gower Street, London, WC1E 6BT, U.K;(3) Department of Crystallography, Birkbeck College, Malet Street, London, WC1E 7HX, U.K |
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Abstract: | Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes. |
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Keywords: | comparative molecular modelling dihydrofolate reductase drug design protein structure |
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