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Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich . (Computational Chemistry and Biochemistry (CCBG))ORCID iD: 0000-0001-8696-3104
2009 (English)In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 4, no 8, 1317-1326 p.Article in journal (Refereed) Published
Abstract [en]

Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high-throughput fragment-based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium- and high-throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.

Place, publisher, year, edition, pages
2009. Vol. 4, no 8, 1317-1326 p.
Keyword [en]
antiplasmodial agents; drug discovery; high-throughput docking; malaria; molecular dynamics
National Category
Other Chemistry Topics Theoretical Chemistry
Research subject
Natural Science
Identifiers
URN: urn:nbn:se:lnu:diva-14221DOI: 10.1002/cmdc.200900078OAI: oai:DiVA.org:lnu-14221DiVA: diva2:445526
Available from: 2011-10-04 Created: 2011-09-16 Last updated: 2015-05-26Bibliographically approved

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CiteExportLink to record
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Citation style
  • apa
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