DIHYDROFOLATE-REDUCTASE - A POTENTIAL-DRUG TARGET IN TRYPANOSOMES ANDLEISHMANIA

Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherap y. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leish mania 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 struc tures and models have been used in the comparison of protozoan, bacter ial and human enzymes in order to highlight the different features tha t can be used in the design of selective anti-protozoan agents. Compar ison has been made between residues present in the active site, the ac cessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high de gree of similarity between protozoan, human and bacterial dihydrofolat e 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 identif ied a larger binding pocket in the protozoan than the human and bacter ial enzymes.