COMPUTATIONAL INSIGHTS INTOSOLUBILITYENHANCEMENT OF KETOCONAZOLE VIACOMPLEXATIONWITH β-CYCLODEXTRIN AND HYDROXYPROPYL-β- CYCLODEXTRIN

Abstract

Ketoconazole is a widely used antifungal drug with poor aqueous solubility, which limits its bioavailabilityandtherapeutic efficacy. Cyclodextrins like β-cyclodextrin (BCD) and its derivative 2-hydroxypropyl-β-cyclodextrin(HPBCD) are recognised for their ability to improve the solubility and stability of drugs. The objective of thisresearch was to explore the binding strength, structural integrity, and solubility improvements of ketoconazolecomplexes with BCD and HPBCD through the use of molecular docking and molecular dynamics simulations. Molecular docking was performed using AutoDock 4.2, followed by 100 ns molecular dynamics simulations inawater/octanol mixture using Amber 16. The assessments included binding energies, hydrogen bonds, hydrophobicinteractions, radius of gyration, and solvent-accessible surface area (SASA) to examine the behaviours of thecomplexes. Docking results showed stronger binding of ketoconazole–BCD (ΔG_bind = –4.56 kcal/mol) comparedto ketoconazole–HPBCD (ΔG_bind = –3.05 kcal/mol). MD simulations revealed that BCD formed a compact andstable complex with a lower radius of gyration, while HPBCD exhibited higher SASA and stronger interactions withwater molecules. Trajectory analyses confirmed that ketoconazole remained more stable in aqueous solution whenencapsulated by HPBCD. The results indicate a trade-off between structural compactness and solubilityenhancement. Although BCD forms a tighter and more rigid complex, HPBCD’s hydrophilic substituents promotegreater solvent accessibility and water affinity, leading to improved solubility of ketoconazole. These findings alignwith previous reports on cyclodextrin derivatives improving dissolution and suggest HPBCD as the more suitableexcipient for aqueous formulations. While BCD forms a tighter inclusion complex, HPBCD provides superior solubility enhancement through increased solvent interactions. These results indicate that HPBCD may be a useful additive to enhance the solubility and bioavailability of ketoconazole.