Computational Profiling of Electronic and Pharmacophoric Features of Felidae Drugs Against Toxoplasma gondii

Toxoplasma gondii , an obligate intracellular protozoan parasite, remains a major zoonotic pathogen with members of the family Felidae serving as its definitive hosts. The limited efficacy and emerging resistance of current anti-toxoplasmic agents necessitate the identification of improved inhibitors targeting the parasite’s key metabolic enzymes. This study leverages a multi-parametric computational approach to evaluate the efficacy of Pyrimethamine, Sulfadiazine, and Clindamycin as potential TS-DHFR (Thymidylate synthase-dihydrofolate reductase) inhibitors targeting Toxoplasma gondii . A series of in silico techniques are employed to thoroughly evaluate their drug-likeness, pharmacokinetics, toxicity, and binding affinity. An analysis of physicochemical properties is performed to evaluate key molecular descriptors, including molecular weight, LogP, hydrogen bond donors and acceptors, topological polar surface area (TPSA), and rotatable bond count, all of which influence the ability of a compound to permeate biological membranes. The POM analysis, integrating PETRA, Osiris, and Molinspiration modules are utilised to compute quantum mechanical descriptors, predict toxicity risks, and estimate bioactivity scores across a range of pharmacological targets. In silico ADMET profiling performed using SwissADME, pkCSM, and ADMETlab that predict toxicity risks, and estimate bioactivity scores across a range of pharmacological targets, such as oral absorption, blood-brain barrier penetration, cytochrome P450 enzyme interactions, and potential toxicological endpoints, including hepatotoxicity, AMES mutagenicity, and skin sensitisation, thereby establishing a preliminary safety profile. Pharmacokinetic simulations are also carried out to forecast oral bioavailability, gastrointestinal absorption, volume of distribution, systemic clearance, and biological half-life. Moreover, molecular docking using AutoDock simulated the interaction of the three drugs with the TS-DHFR active site, evaluating binding energies, types of interactions hydrogen bonds, hydrophobic contacts, π-π stacking), and identifying key amino acid residues involved in ligand binding. Finally, Density Functional Theory (DFT) studies are conducted to complement the molecular-level understanding. These involved geometry optimization, Molecular Electrostatic Potential (MEP) mapping, Mulliken charge distribution analysis, and frontier molecular orbital (HOMO-LUMO) evaluations, providing insights into the electronic properties, reactivity, and stability of the ligands. This integrative computational framework provides a comprehensive in silico evaluation of the three clinically relevant potential drugs for systematic drug repurposing and optimisation strategies aimed at treating toxoplasmosis through TS-DHFR inhibition within wild and domestic members of Family Felidae .