Structure-based Design of Novel Small-Molecule Inhibitors of Plasmodium falciparum

publication · 8 years ago
by Sandhya Kortagere, William J. Welsh, Joanne M. Morrisey, Thomas Daly, Ijeoma Ejigiri, Photini Sinnis, Akhil B. Vaidya, Lawrence W. Bergman (Drexel University College of Medicine)
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 EC50 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.
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