In silico analysis of Anacardium occidentale phytochemicals: pharmacokinetics, molecular docking, and dynamics of Cryptococcus neoformans enzymes

Abstract This study evaluated in silico the antifungal potential of phytochemicals from the leaves of Anacardium occidentale (cashew tree) against key enzymatic targets: farnesyltransferase (CnFTase), beta-carbonic anhydrase (β-CA), and adenylosuccinate synthetase (AdSS) from Cryptococcus neoformans . Molecular docking simulations were conducted to evaluate the binding affinity of selected compounds to key enzymatic targets. The protein structures were retrieved from the Protein Data Bank (PDB) and prepared using AutoDockTools™, while molecular docking was performed with AutoDockVina. Molecular dynamics simulation was performed using the iMODS server, in order to check the stability as well as mobility in the receptor-ligand complexes following molecular docking. Additionally, ADME-Tox properties were predicted using a consensus approach combining ADMETlab 3.0 and ADMET-AI, assessing parameters such as permeability (PAMPA), metabolism (CYP450), and clearance ( Cl int, u , Cl Micro , Cl Hepa ). The structural complexity of the ligands was analyzed using the MCE18 score, allowing the identification of compounds with an optimal balance between drug-likeness and synthetic accessibility. Notably, quercetin 3-galactoside, tricetin 3’-xyloside, and kaempferol 4’-glucoside exhibited favorable pharmacokinetic profiles and docking affinities, suggesting their potential as antifungal candidates. A PAMPA profile is estimated for these compounds based on a moderate permeability in more selective cells (High Papp MDCK) and low hepatic clearance, resulting from metabolic stability. Molecular docking studies showed that lead compounds have excellent affinity and specificity for the enzymes CnFTase and AdSS (affinity energy <-6.0 kcal/mol), interacting with the binding sites of the drug Fluconazole. Molecular dynamics simulations indicated a smaller conformational torsion of the Cα of the CnFTase and AdSS structures, suggesting that collective movements for both protein-ligand complexes are stable. The results suggest that these lead compounds are a starting point for new glycosylated drugs inhibiting Cryptococcus neoformans .