Supplemental material for: Pharmacokinetics, Quantum Chemistry, and Molecular Modeling Analysis of Six Potential Drug Candidates for Chagas Disease: Posaconazole, K777, Phenarimol Derivative, BZTS, Isoxazole Analog, and derivative of 4-arylaminonoline-3-carbonitrile

Aim: Chagas disease, caused by Trypanosoma cruzi, lacks safe and effective therapies, especially in the chronic phase. This study aimed to prioritize antichagasic candidates by integrating in silico pharmacokinetics, ADMET (absorption, distribution, metabolism, excretion and toxicity) profile and molecular modeling, focusing on cruzain as a key target.

Materials & Methods: Six prototypes: posaconazole, vinyl sulfone peptide analog, phenarimol derivative, 4-nitrobenzaldehyde thiosemicarbazone (BZTS), an isoxazole analog and a 4-arylaminonoline-3-carbonitrile derivative; were profiled using multi-platform ADMET prediction, quantum chemical calculations, molecular docking and QM/MM (Quantum Mechanics/Molecular Mechanics) refinement of cruzain complexes.

Results: BZTS emerged as the lead candidate. It showed high predicted human intestinal absorption, balanced aqueous solubility, optimal plasma protein binding and limited interaction with major cytochrome P450 isoforms, indicating favorable exposure and a low risk of drug–drug interactions. Toxicity models indicated reduced risk of cardiotoxicity, mutagenicity, carcinogenicity and hepatotoxicity compared with the other prototypes. Quantum descriptors supported a stable but reactive electronic structure, with a HOMO–LUMO gap of 2.482 eV. Docking and QM/MM analyses revealed strong binding of BZTS to cruzain, with key contacts involving residues GLU208, MET68, LEU67 and ASN69.

Conclusion: An integrated in silico pipeline consistently identified BZTS as the most promising antichagasic prototype, combining advantageous ADMET properties with favorable quantum-chemical features and cruzain binding, and supporting its prioritization for experimental validation.