Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach

Sandhya Kortagere, Ernest Mui, Rima McLeod, William J. Welsh

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)403-411
Number of pages9
JournalJournal of Computer-Aided Molecular Design
Issue number5
StatePublished - May 2011

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry


  • Cytotoxicity
  • Drug design
  • Hybrid structure based method
  • Toxoplasma gondii


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