In Silico Analysis of Pinocembrin Inclusion Complexes with beta-Cyclodextrin and Hydroxypropyl-beta-Cyclodextrin Using DFT and Molecular Docking

Abstract

Pinocembrin is a naturally occurring flavanone found in medicinal plants, particularly Boesenbergia rotunda, with promising pharmacological activities; however, its poor aqueous solubility limits its pharmaceutical application. Cyclodextrin inclusion complexation represents a potential strategy to improve the solubility characteristics of poorly water-soluble compounds. This study aimed to investigate the molecular characteristics and inclusion behavior of pinocembrin with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HPβ-CD) using an in silico approach combining ADME prediction, Density Functional Theory (DFT), and molecular docking analysis. The physicochemical properties, drug-likeness, and pharmacokinetic profiles of pinocembrin were evaluated using SwissADME and pkCSM. Geometry optimization and electronic properties were analyzed using DFT at the B3LYP/6-311G(d,p) level of theory. Molecular docking simulations were performed using AutoDock Vina to evaluate binding orientations, binding affinities, and intermolecular interactions between pinocembrin and cyclodextrin cavities. The ADME analysis indicated that pinocembrin exhibited favorable drug-like properties and pharmacokinetic characteristics, although low aqueous solubility remained a critical challenge. DFT analysis revealed a stable optimized structure with an energy gap of 5.08 eV and a dipole moment of 2.8912 Debye. Molecular docking demonstrated that pinocembrin could be accommodated within both β-CD and HPβ-CD cavities through different inclusion orientations. The A-form orientation showed the most favorable interaction, with the pinocembrin–HPβ-CD complex exhibiting a slightly more favorable predicted binding affinity (−5.9 kcal/mol) than pinocembrin–β-CD (−5.6 kcal/mol); However, the 0.3 kcal/mol difference is small and within the expected uncertainty of molecular docking. These findings provide molecular insights into pinocembrin–cyclodextrin inclusion complexes and suggest the potential application of HPβ-CD as a carrier for improving the solubility characteristics of pinocembrin.