Abstract
The investigation of bioactive phytochemicals from Anacardium occidentale (cashew) nut has attracted increasing interest, particularly due to their potential antifungal properties against Cryptococcus neoformans. In this study, molecular docking analysis were employed to assess the interaction strength of selected compounds with crucial enzymatic targets, including farnesyltransferase (CnFTase), beta-carbonic anhydrase (β-CA), and adenylosuccinate synthetase (AdSS). 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. To evaluate the pharmacokinetic behavior, a multiparametric optimization (MPO) approach was applied, considering parameters such as membrane permeability (PAMPA), metabolic processing via cytochrome P450 (CYP450) enzymes, and clearance rates (Cl(int, u), Cl(Micro), Cl(Hepa)). The degree to which the ligands resemble drugs was evaluated using drug-likeness scores (QED and MCE-18). Protein structures were retrieved from the Protein Data Bank and preprocessed using AutoDockTools™, with docking simulations conducted via AutoDock Vina. The methodology incorporated a Lamarckian Genetic Algorithm combined with an exhaustive search strategy. In the course of the present study, 13 compounds were examined, and four of these were identified as leads: catechin, epicatechin, naringenin, and pinostrobin. This determination was made in accordance with the MPO criteria. These molecules exhibited both high permeability in Caco-2 and MDCK models and favorable hydration free energies (ΔG(hyd) ≤ -5.0 kcal/mol). Futhermore, naringenin and pinostrobin were demonstrated to undergo metabolic transformation by CYP450 enzymes in hepatic microsomes, indicating limited metabolic stability. The docking results indicated strong binding affinities (E(A≤) -6.0 kcal/mol) to CnFTase and AdSS, underscoring their potential as enzyme inhibitors through interactions within the active site, including residues associated with fluconazole binding site. 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 antifungal drugs inhibiting C. neoformans. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00203-026-04814-9.