Journal article
Structure-based Design of Novel Small-Molecule Inhibitors of Plasmodium falciparum
Journal of chemical information and modeling, v 50(5), pp 840-849
24 May 2010
PMID: 20426475
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 co-crystal 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 fifteen 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 eight compounds with EC
50
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 invasive features of the malarial parasite.
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Details
- Title
- Structure-based Design of Novel Small-Molecule Inhibitors of Plasmodium falciparum
- Creators
- Sandhya Kortagere - Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, USAWilliam J Welsh - Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ, USAJoanne M Morrisey - Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, USAThomas Daly - Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, USAIjeoma Ejigiri - Department of Molecular Parasitology, New York University School of Medicine, New York, NY, USAPhotini Sinnis - Department of Molecular Parasitology, New York University School of Medicine, New York, NY, USAAkhil B Vaidya - Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, USALawrence W Bergman - Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, USA
- Publication Details
- Journal of chemical information and modeling, v 50(5), pp 840-849
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; [Retired Faculty]
- Web of Science ID
- WOS:000277911600012
- Scopus ID
- 2-s2.0-77952780117
- Other Identifier
- 991014877762204721
UN Sustainable Development Goals (SDGs)
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Multidisciplinary
- Computer Science, Information Systems
- Computer Science, Interdisciplinary Applications