Targeting Trichophyton rubrum with phytochemicals: a computational approach for antifungal drug discovery

Trichophyton rubrum , the leading cause of dermatophytosis, poses a growing public health concern due to its chronicity, recurrence, and resistance to existing antifungal drugs. This study employed a computational pipeline that integrated target selection, structural modeling, molecular docking, pharmacokinetic profiling, molecular dynamics simulations (MDS), and free energy calculations to identify phytochemicals with antifungal potential. Four extracellular proteins, including 1,3-β-glucanosyltransferase, CFEM domain-containing protein, galactomannoprotein, and LysM domain-containing protein, were selected as targets based on their antigenicity, extracellular localization, and lack of human homology. Docking revealed strong interactions, with cryptoxanthin showing the highest affinity (–8.7 kcal/mol) for glucanosyltransferase and LysM, while chalcones, anthocyanins (delphinidin, cyanidin), and theaflavin emerged as additional potent binders. ADMET analysis refined candidate selection, highlighting chalcones and delphinidin as the most promising compounds due to favorable absorption, bioavailability, and safety profiles, unlike carotenoids, which showed poor pharmacokinetics and toxicity risks. MDS over 200 ns revealed stable binding in all four complexes, with average ligand RMSDs ranging from 4.07 Å (delphinidin) to 30.71 Å (silymarin), supported by hydrogen bonds, hydrophobic interactions, and water bridges; MM-GBSA calculations showed favorable binding affinities (ΔG bind from –53.18 to –64.00 kcal/mol), dominated by van der Waals and Coulombic forces. PCA and DCCM analyses indicated ligand-specific conformational dynamics, with delphinidin promoting the highest structural stability and rigidity. Silymarin and chalcones induced greater flexibility and collective motions in their respective protein targets. These findings position chalcones and anthocyanins as promising scaffolds for antifungal drug development, reinforcing the potential of phytochemicals to inspire safer and more effective therapies against T. rubrum .