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Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
The use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR.
Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance.
Comparison of crystal structures of PvDHFR from wild-type and the Pyr-resistant strain as complexes with NADPH and Pyr or its analog lacking p-Cl (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme is mainly responsible for the reduction in binding of Pyr.
Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities.
These compounds in the Pyr and Cyc series exhibit low and moderate cytotoxicity to nontumor (Vero) and tumor (KB, BC) cell lines and are therefore potential candidates for further development as antimalarials.
Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum.
A number of compounds were identified with high affinities for both wild-type and mutant DHFRs, with very low to no affinity to human DHFR, some of these compounds show good antimalarial activities against pyrimethamine-resistant P. falciparum containing the mutantDHFRs with low cytotoxicity to three mammalian cell lines.
Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors
New inhibitors with high affinity against both wild-type and mutant enzymes have been designed and synthesized, some of which have very potent antimalarial activities against drug-resistant P. falciparum bearing the mutant enzymes.
C-16 artemisinin derivatives and their antimalarial and cytotoxic activities: syntheses of artemisinin monomers, dimers, trimers, and tetramers by nucleophilic additions to artemisitene.
Nucleophilic additions of lithium keto and ester enolates and mono- and bifunctional Grignard reagents to artemisitene provided C-16-derived artemisinin monomers, dimers, trimers, and tetramers whose
Stoichiometric selection of tight-binding inhibitors by wild-type and mutant forms of malarial (Plasmodium falciparum) dihydrofolate reductase.
A simple method for screening combinatorial and other libraries of inhibitors of malarial (Plasmodium falciparum) dihydrofolate reductase (PfDHFR) has been developed, based on the affinities of the inhibitors with the enzyme and a good correlation was found between the inhibition constants (Ki values) and the extent of binding of inhibitors to wild-type, double and quadruple mutant patients.
Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance
The S108N mutation of dihydrofolate reductase (DHFR) renders Plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor.