Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors.

摘要: Dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Plasmodium falciparum, a validated target for antifolate antimalarials, is dimeric enzyme with interdomain interactions significantly mediated by the junction region as well Plasmodium-specific additional sequences (inserts) in DHFR domain. The X-ray structures of both wild-type and mutant enzymes associated drug resistance, complex either which lost, or still retains, effectiveness mutants, reveal features explain basis resistance resulting mutations around active site. Binding rigid inhibitors like pyrimethamine cycloguanil to site affected steric conflict side-chains mutated residues 108 16, changes main chain configuration. role important on binding substrates was further elucidated site-directed random mutagenesis studies. Guided structure modes inhibitor binding, new high affinity against have been designed synthesized, some very potent anti-malarial activities drug-resistant P. falciparum bearing enzymes.