Abstract:
:Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 --> Arg + Ser-117 --> Asn) 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, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes.
journal_name
Proc Natl Acad Sci U S Aauthors
Kongsaeree P,Khongsuk P,Leartsakulpanich U,Chitnumsub P,Tarnchompoo B,Walkinshaw MD,Yuthavong Ydoi
10.1073/pnas.0501747102keywords:
subject
Has Abstractpub_date
2005-09-13 00:00:00pages
13046-51issue
37eissn
0027-8424issn
1091-6490pii
0501747102journal_volume
102pub_type
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