Identification of the optimal third generation antifolate against P. falciparum and P. vivax.
Inhibitors of dihydrofolate reductase (DHFR) have been mainstays in the treatment of falciparum malaria. Resistance to one of these antifolates, pyrimethamine, is now common in Plasmodium falciparum populations. Antifolates have not traditionally been recommended for treatment of vivax malaria. However, recent studies have suggested that a third-generation antifolate, WR99210, is remarkably effective even against highly pyrimethamine-resistant parasites from both species. Two methods were used to identify a compound that is effective against quadruple mutant alleles from P. falciparum (N51I/C59R/S108N/I164L) and from Plasmodium vivax (57L/111L/117T/173F). The first was simple yeast system used to screen a panel of WR99210 analogs. The biguanide prodrug, JPC-2056, of the 2-chloro-4-trifluoromethoxy analog of WR99210 was effective against both the P. falciparum and P. vivax enzymes, and has been selected for further development. The second method compared the analogs in silico by docking them in the known structure of the P. falciparum DHFR-thymidylate synthase. The program reproduced well the position of the triazine ring, but the calculated energies of ligand binding were very similar for different compounds and therefore did not reproduce the observed trends in biological activity. The WR99210 family of molecules is flexible due to a long bridge between the triazine ring and the substituted benzene. During docking, multiple conformations were observed for the benzene ring part of the molecules in the DHFR active site, making computer-based predictions of binding energy less informative than for more rigid ligands. This flexibility is a key factor in their effectiveness against the highly mutant forms of DHFR.
Hunt
Sonia Y
SY
Department of Genome Sciences, University of Washington, Box 357730, Seattle, WA 98195-7730, USA.
Detering
Carsten
C
Varani
Gabriele
G
Jacobus
David P
DP
Schiehser
Guy A
GA
Shieh
Hong-Ming
HM
Nevchas
Isabelle
I
Terpinski
Jacek
J
Sibley
Carol Hopkins
CH
D000483:Alleles; D000818:Animals; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D010966:Plasmodium vivax / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D005493:Folic Acid Antagonists; D015800:Protozoan Proteins; D014227:Triazines; D013762:Tetrahydrofolate Dehydrogenase