Antimalarial drug discovery: development of inhibitors of dihydrofolate reductase active in drug resistance

In view of widespread drug resistance in Plasmodium falciparum, new antimalarials are needed. Modelling techniques are being applied with some success to the design of drugs targeting dihydrofolate reductase (DHFR), and screening systems using recombinant enzyme are producing valuable data. The author reviews the interaction of inhibitors with probable active-site residues and examines new approaches. As the interaction of straight rigid drugs, like pyrimethamine, with the binding site of plasmodial DHFR is inhibited by the bulky Ser108→Asn resistance mutation, more flexible drugs, such as trimethoprim, may have a role in areas where this mutation is found.