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

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 IC(50) value ~500 nM against T. gondii. Among the 16 structural analogs of C3-21 tested thus far, nine additional compounds were identified with IC(50) 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.

Dissecting the molecular assembly of the Toxoplasma gondii MyoA motility complex

“…on calcium coordination and a prescribed order of binding to support cooperativity. Structural and binding data of the MLC1-MyoA complex may enable the expansion and refinement of current efforts to develop peptidomimetic and smallmolecule inhibitors that interfere with assembly of the apicomplexan MyoA complex (34,41).…”

Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry

“…Starting from their study on MTIP-MyoA that provided new antimalarial agents (see Section 4.6.1) and supported by the hypothesis that the MTIP-MyoA complex is essential also in the in T. gondii survival, Kortagere and co-workers constructed a hypothetical structure model of this complex and used the HSB method to screen for small molecule drugs against toxoplasmosis [106]. In the absence of the X-ray crystal structure for the T. gondii MTIP-MyoA complex, homology modeling techniques were employed to build a structural model of the T. gondii MTIP-MyoA_tail complex using the published X-ray crystal structure of Plasmodium MTIP-MyoA tail as the template.…”

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

“…This parasite target is part of an important signaling pathway involved in gliding, a required motion for T. gondii to cross the host cell's plasma membrane (26). Other compounds that affect both invasion and egress are dinitroanilines (27) and diaryl ureas (28), which are suspected to destabilize microtubules and myosin tail interactions, respectively.…”