Publication: Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors
Issued Date
2003-07-03
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ISSN
00222623
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2-s2.0-0037784010
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Medicinal Chemistry. Vol.46, No.14 (2003), 2834-2845
Suggested Citation
Giulio Rastelli, Sara Pacchioni, Worachart Sirawaraporn, Rachada Sirawaraporn, Marco Daniele Parenti, Anna Maria Ferrari Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors. Journal of Medicinal Chemistry. Vol.46, No.14 (2003), 2834-2845. doi:10.1021/jm030781p Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/20711
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Title
Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors
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Abstract
Plasmodium falciparum dihydrofolate reductase (PfDHFR) is an important target for antimalarial chemotherapy. Unfortunately, the emergence of resistant parasites has significantly reduced the efficiency of classical antifolate drugs such as cycloguanil and pyrimethamine. In this study, an approach toward molecular docking of the structures contained in the Available Chemicals Directory (ACD) database to search for novel inhibitors of PfDHFR is described. Instead of docking the whole ACD database, specific 3D pharmacophores were used to reduce the number of molecules in the database by excluding a priori molecules lacking essential requisites for the interaction with the enzyme and potentially unable to bind to resistant mutant PfDHFRs. The molecules in the resulting "focused" database were then evaluated with regard to their fit into the PfDHFR active site. Twelve new compounds whose structures are completely unrelated to known antifolates were identified and found to inhibit, at the micromolar level, the wild-type and resistant mutant PfDHFRs harboring A16V, S108T, A16V + S108T, C59R + S108N + I164L, and N51I + C59R + S108N + I164L mutations. Depending on the functional groups interacting with key active site residues of the enzyme, these inhibitors were classified as N-hydroxyamidine, hydrazine, urea, and thiourea derivatives. The structures of the complexes of the most active inhibitors, as refined by molecular mechanics and molecular dynamics, provided insight into how these inhibitors bind to the enzyme and suggested prospects for these novel derivatives as potential leads for antimalarial development.