Elucidation of sulfadoxine resistance with structural models of the bifunctional Plasmodium falciparum dihydropterin pyrophosphokinase-dihydropteroate synthase

Bioorganic & Medicinal Chemistry
Tjaart A P de BeerFourie Joubert

Abstract

Resistance of the most virulent human malaria parasite, Plasmodium falciparum, to antifolates is spreading with increasing speed, especially in Africa. Antifolate resistance is mainly caused by point mutations in the P. falciparum dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) target proteins. Homology models of the bifunctional P. falciparum dihydropterin pyrophosphokinase-dihydropteroate synthase (PPPK-DHPS) enzyme as well as the separate domains complete with bound substrates were constructed using the crystal structures of Saccharomyces cerevisiae (PPPK-DHPS), Mycobacterium tuberculosis (DHPS), Bacillus anthracis (DHPS), and Escherichia coli (PPPK) as templates. The resulting structures were subsequently solvated and refined using molecular dynamics. The active site residues of DHPS are highly conserved in S. cerevisiae, M. tuberculosis, E. coli, S. aureus, and B. anthracis, an attribute also shared by P. falciparum DHPS. Sulfadoxine was superimposed into the equivalent position of the p-aminobenzoic acid substrate and its binding parameters were refined using minimization and molecular dynamics. Sulfadoxine appears to interact mainly with P. falciparum DHPS mainly through hydrophobic interactions. Ratio...Continue Reading

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Citations

Dec 16, 2010·Future Microbiology·Ingrid B Müller, John E Hyde
Mar 19, 2013·Molecular and Biochemical Parasitology·Ingrid B Müller, John E Hyde
Apr 28, 2009·Parasitology International·Toshihiro MitaKiyoshi Kita
Sep 11, 2007·The FEBS Journal·John E Hyde
Nov 9, 2016·International Journal for Parasitology. Drugs and Drug Resistance·Mary C OguikeCally Roper

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