Abstract
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 language | English (US) |
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Pages (from-to) | 840-849 |
Number of pages | 10 |
Journal | Journal of Chemical Information and Modeling |
Volume | 50 |
Issue number | 5 |
DOIs | |
State | Published - May 24 2010 |
Externally published | Yes |
ASJC Scopus subject areas
- General Chemistry
- General Chemical Engineering
- Computer Science Applications
- Library and Information Sciences