Structure-based design of novel small-molecule inhibitors of plasmodium falciparum

Sandhya Kortagere, William J. Welsh, Joanne M. Morrisey, Thomas Daly, Ijeoma Ejigiri, Photini Sinnis, Akhil B. Vaidya, Lawrence W. Bergman

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Malaria is endemic in most developing countries, with nearly 500 million cases estimated to occur each year. The need to design a new generation of antimalarial drugs that can combat the most drug-resistant forms of the malarial parasite is well recognized. In this study, we wanted to develop inhibitors of key proteins that form the invasion machinery of the malarial parasite. A critical feature of host-cell invasion by apicomplexan parasites is the interaction between the carboxy terminal tail of myosin A (MyoA) and the myosin tail interacting protein (MTIP). Using the cocrystal structure of the Plasmodium knowlesi MTIP and the MyoA tail peptide as input to the hybrid structure-based virtual screening approach, we identified a series of small molecules as having the potential to inhibit MTIP-MyoA interactions. Of the initial 15 compounds tested, a pyrazole-urea compound inhibited P. falciparum growth with an EC 50 value of 145 nM. We screened an additional 51 compounds belonging to the same chemical class and identified 8 compounds with EC50 values less than 400 nM. Interestingly, the compounds appeared to act at several stages of the parasite's life cycle to block growth and development. The pyrazole-urea compounds identified in this study could be effective antimalarial agents because they competitively inhibit a key protein-protein interaction between MTIP and MyoA responsible for the gliding motility and the invasive features of the malarial parasite.

Original languageEnglish (US)
Pages (from-to)840-849
Number of pages10
JournalJournal of Chemical Information and Modeling
Issue number5
StatePublished - May 24 2010
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences


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