Quantitative Structure–Activity Relationship Modeling and Molecular Docking Studies of TgCDPK1 Inhibitors in Toxoplasma gondii

Abstract

Toxoplasma gondii is a globally prevalent protozoan parasite responsible for severe health complications, particularly in immunocompromised individuals and during congenital infections. Existing treatments are limited by suboptimal efficacy and significant side effects, highlighting the urgent need for novel therapeutic strategies. Calcium-dependent protein kinase 1 (TgCDPK1) has emerged as a promising drug target due to its critical role in T. gondii pathogenesis and structural divergence from human kinases. This study integrates quantitative structure–activity relationship (QSAR) modeling and molecular docking to identify and prioritize potent TgCDPK1 inhibitors. A robust QSAR model was developed from a data set of 152 ligands, leveraging a systematic feature selection process to identify 23 key molecular descriptors predictive of inhibitory activity (R = 0.895, R² = 0.802). Molecular docking studies further characterized the binding interactions of top-ranked ligands, revealing strong binding affinities and favorable ADMET profiles. Notably, compound L03, identified as a substituted imidazopyrimidine derivative, demonstrated exceptional binding energy (−176.794 kcal/mol) and stability within the TgCDPK1 active site. Key interactions with Asp210(A) through hydrogen bonds and hydrophobic contacts were instrumental in its high binding affinity, underscoring its potential as a lead compound. These findings provide a comprehensive framework for rational drug design, combining computational approaches to accelerate the discovery of selective and efficacious anti-toxoplasma agents targeting TgCDPK1. This integrated methodology represents a significant advancement toward addressing the unmet clinical needs of toxoplasmosis treatment.