Publication: Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: Structural basis of antifolate resistance
Issued Date
2000-05-01
Resource Type
ISSN
09680896
Other identifier(s)
2-s2.0-0034074798
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Mahidol University
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SCOPUS
Bibliographic Citation
Bioorganic and Medicinal Chemistry. Vol.8, No.5 (2000), 1117-1128
Suggested Citation
Giulio Rastelli, Worachart Sirawaraporn, Pornthep Sompornpisut, Tirayut Vilaivan, Sumalee Kamchonwongpaisan, Rachel Quarrell, Gordon Lowe, Yodhathai Thebtaranonth, Yongyuth Yuthavong Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: Structural basis of antifolate resistance. Bioorganic and Medicinal Chemistry. Vol.8, No.5 (2000), 1117-1128. doi:10.1016/S0968-0896(00)00022-5 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/25874
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Title
Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: Structural basis of antifolate resistance
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.