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

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• 作者：Sandhya Kortagere ; William J. Welsh ; Joanne M. Morrisey ; Thomas Daly ; Ijeoma Ejigiri ; Photini Sinnis ; Akhil B. Vaidya ; Lawrence W. Bergman
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2010
• 出版时间：May 24, 2010
• 年：2010
• 卷：50
• 期：5
• 页码：840-849
• 全文大小：451K
• 年卷期：v.50,no.5(May 24, 2010)
• ISSN：1549-960X

文摘

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 ECb>50b> value of 145 nM. We screened an additional 51 compounds belonging to the same chemical class and identified 8 compounds with ECb>50b> 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.