Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: Structural basis of antifolate resistance

The nature of the interactions between Plasmodium falciparum dihydrofolate reductase (pfDHFR) and antimalarial antifolates, i.e., pyrimethamine (Pyr), cycloguanil (Cyc) and WR99210 including some of their analogues, was inves tigated by molecular modeling in conjunction with the determination of the inhibition constants (K-i). A three-dimensional structural model of pfDHFR was constructed using multiple sequence alignment and homology modeling pro cedures, followed by extensive molecular dynamics calculations. Mutations a t amino acid residues 16 and 108 known to be associated with antifolate res istance were introduced into the structure, and the interactions of the inh ibitors with the enzymes were assessed by docking and molecular dynamics fo r both wild-type and mutant DHFRs. The K-i values of a number of analogues tested support the validity of the model. A 'steric constraint' hypothesis is proposed to explain the structural basis of the antifolate resistance. ( C) 2000 Elsevier Science Ltd. All rights reserved.