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Title: Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: Structural basis of antifolate resistance
Authors: Giulio Rastelli
Worachart Sirawaraporn
Pornthep Sompornpisut
Tirayut Vilaivan
Sumalee Kamchonwongpaisan
Rachel Quarrell
Gordon Lowe
Yodhathai Thebtaranonth
Yongyuth Yuthavong
Universita degli Studi di Modena e Reggio Emilia
Mahidol University
Chulalongkorn University
Thailand National Center for Genetic Engineering and Biotechnology
University of Oxford
Keywords: Biochemistry, Genetics and Molecular Biology;Chemistry;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-May-2000
Citation: Bioorganic and Medicinal Chemistry. Vol.8, No.5 (2000), 1117-1128
Abstract: The nature of the interactions between Plasmodium falciparum dihydrofolate reductase (pfDHFR) and antimalarial antifolates, i.e., pyrimethamine (Pyr), cycloguanil (Cyc) and WR99210 including some of their analogues, was investigated by molecular modeling in conjunction with the determination of the inhibition constants (K(i)). A three-dimensional structural model of pfDHFR was constructed using multiple sequence alignment and homology modeling procedures, followed by extensive molecular dynamics calculations. Mutations at amino acid residues 16 and 108 known to be associated with antifolate resistance were introduced into the structure, and the interactions of the inhibitors with the enzymes were assessed by docking and molecular dynamics for both wild-type and mutant DHFRs. The K(i) values of a number of analogues tested support the validity of the model. A 'steric constraint' hypothesis is proposed to explain the structural basis of the antifolate resistance. (C) 2000 Elsevier Science Ltd.
ISSN: 09680896
Appears in Collections:Scopus 1991-2000

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