Enhancing aqueous solubility of a psoralen derivative via cyclodextrin inclusion complexation: In silico and in vitro study

Gulzaib  BASHARAT; Saba  ALI; Pattharamon  CHAIKHUN; Choosak  JAROENRIT; Kuakarun  KRUSONG; Thanthapatra  BUNCHUAY; Tanatorn  KHOTAVIVATTANA; Thanyada RUNGROTMONGKOL

doi:10.55713/jmmm.v36i3.2610

Authors

Gulzaib BASHARAT Program in Bioinformatics and Computational Biology, College of Interdisciplinary and Integrative Studies, Chulalongkorn University, Bangkok 10330, Thailand
Saba ALI Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Pattharamon CHAIKHUN Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Choosak JAROENRIT Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Kuakarun KRUSONG Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Thanthapatra BUNCHUAY Department of Chemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
Tanatorn KHOTAVIVATTANA Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Thanyada RUNGROTMONGKOL Program in Bioinformatics and Computational Biology, College of Interdisciplinary and Integrative Studies, Chulalongkorn University, Bangkok 10330, Thailand / Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

DOI:

https://doi.org/10.55713/jmmm.v36i3.2610

Keywords:

Psoralen derivative, β-Cyclodextrins, Inclusion complex, Computational study, Experimental validation

Abstract

N-(4-Bromobenzoyl)-8-methoxypsoralen-4-amine (BNB) is a psoralen derivative with potent cytotoxic activity against breast cancer cells but with limited pharmaceutical application and therapeutic potential due to its extremely low aqueous solubility. To overcome this limitation, β-cyclodextrin (βCD) and its derivatives dimethyl-βCD (DMβCD), hydroxypropyl-βCD (HPβCD), and sulfobutylether-βCD (SBEβCD) were investigated as carriers to enhance BNB's aqueous solubility via cyclodextrin inclusion complexation. A combined computational–experimental strategy was employed, integrating molecular docking, 500-ns all-atom molecular dynamics simulations in quintuplicate runs (2.5 µs in total), and experimental validation by phase solubility analysis, scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). Docking and simulations revealed stable host–guest interactions, with SBEβCD showing the most favorable binding free energies, the highest number of atomic contacts, and the lowest solvent-accessible surface area, indicative of deep and stable encapsulation. Phase solubility studies corroborated these findings, with BNB/SBEβCD exhibiting the highest apparent stability constant. The formation of the inclusion complex was further supported by SEM and DSC, which revealed pronounced morphological changes and thermal evidence consistent with encapsulation, including suppression of the BNB melting endotherm. ¹H NMR spectroscopic analysis further confirmed complex formation through observed peak broadening and chemical shift perturbations upon complexation. Collectively, these results identify SBEβCD as a highly effective carrier for BNB, offering a rational approach to improve solubility through stable complex formation, and supporting its potential as a promising chemotherapeutic candidate for breast cancer treatment.

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