Journal article
Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach
Journal of computer-aided molecular design, v 25(5), pp 403-411
May 2011
PMID: 21359560
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Toxoplasma (T.) gondii, the causative agent of toxoplasmosis, is a ubiquitous opportunistic pathogen that infects individuals worldwide, and is a leading cause of severe congenital neurologic and ocular disease in humans. No vaccine to protect humans is available, and hypersensitivity and toxicity limit the use of the few available medicines. Therefore, safer and more effective medicines to treat toxoplasmosis are urgently needed. Using the Hybrid Structure Based (HSB) method, we have previously identified small molecule inhibitors of P. falciparum that seem to target a novel protein–protein interaction between the Myosin tail interacting protein and myosin light chain. This pathway has been hypothesized to be involved in invasion of host erythrocytes by the parasite and is broadly conserved among the apicomplexans. Guided by similar computational drug design approaches, we investigated this series of small molecules as potential inhibitors of T. gondii. Compound C3-21, identified as the most active inhibitor in this series, exhibited an IC50 value ~500 nM against T. gondii. Among the 16 structural analogs of C3-21 tested thus far, nine additional compounds were identified with IC50 values <10.0 μM. In vitro assays have revealed that C3-21 markedly limits intracellular growth of T. gondii tachyzoites, but has no effect on host cell human foreskin fibroblasts (HFF) at concentrations more than a log greater than the concentration that inhibits the parasites.
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Details
- Title
- Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach
- Creators
- Sandhya Kortagere - Department of Microbiology and Immunology Drexel University College of Medicine Philadelphia PA 19129 USAErnest Mui - The University of Chicago 5841 South Maryland Avenue, MC 2114, Room S-206 Chicago IL 60637 USARima McLeod - The University of Chicago 5841 South Maryland Avenue, MC 2114, Room S-206 Chicago IL 60637 USAWilliam Welsh - University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School 675 Hoes Lane Piscataway NJ 08854 USA
- Publication Details
- Journal of computer-aided molecular design, v 25(5), pp 403-411
- Publisher
- Springer Netherlands; Dordrecht
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000291261700002
- Scopus ID
- 2-s2.0-80051706045
- Other Identifier
- 991014877758504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Biophysics
- Computer Science, Interdisciplinary Applications