Deciphering ophthalmic adaptive inhibitors targeting RON4 of Toxoplasma gondii: An integrative in silico approach.

AIMS: Toxoplasma gondii (T. gondii) is an intracellular Apicomplexan parasite and a causative agent of toxoplasmosis in human. Its parasitic invasion leads to encephalitis, uveitis, chorioretinitis and congenital infection. Host invasion by T. gondii is mediated by Moving junction (MJ) complex formed by secretory proteins such as micronemes and Rhoptry Neck proteins (RONs). Among these secretory proteins, RON4 shows major interactions with RON2 and RON5 of MJ complex and is also found to facilitate invasion by interacting with β-tubulin of the host. Therefore, drug targeting of RON4 is considered to be an effective modality to inhibit host invasion.

MAIN METHODS: Hence, in this study, we have implemented High throughput virtual screening (HTVS) against predicted novel druggable cavity on RON4, in order to prioritize potential inhibitors. This study also specifically focuses on identifying potential drugs that are ocular accommodative towards targeting ocular toxoplasmosis. Thus, the small molecules resulting from HTVS were subjected to stringent multi-level precision screening which involves PASS prediction, Density functional theory analysis, Binding Free Energy Calculations and stability of complex formation during molecular dynamics simulation to prioritize the potential hits.

KEY FINDINGS: Among the compounds from NCI chemical library, five (338683, 333739, 686585, 159706, 405935) were found to surpass all the stringent filtration criteria.

SIGNIFICANCE: Based on comparatively analysis, it was inferred that 333739 (benzyl 2-((2-(((benzyloxy) carbonyl) amino)-3-hydroxybutanoyl) amino) propanoate) to be highly potential in comparison to other compounds and shall prove to be an efficient inhibitor of RON4 in ocular toxoplasmosis.