Evaluation of molecular inclusion of azole antifungals by β-cyclodextrin using computational molecular approach

Fungal infection is an emerging global concern highlighting diseases like pneumonia, invasive candidiasis, chronic pulmonary aspergillosis, and meningitis. But major concern is development of antifungal drug resistance, necessitating novel pharmacological solutions. Azoles, particularly fluconazole and related compounds, are emphasized for their systemic efficacy via inhibition of CYP51, altering fungal cell membrane sterols. So, in this work we theoretically investigated the effect of complexation of azoles with β-cyclodextrin (β-CD), focusing on improving solubility and bioavailability. Using molecular docking, the interaction between azoles and β-CD is analyzed, predicting stability and binding energies. Docking studies elucidate specific binding modes and hydrogen bonding interactions, while PM3 calculations provide insights into electronic structures and properties such as HOMO–LUMO energy gaps, chemical potential, hardness, and electrophilicity. Our findings indicate that fluconazole-β-CD complexes, particularly FCZ-βCD2, exhibit stability and promising development potential due to low energy and favorable binding characteristics. The antifungal spectrum of all the inclusion complexes was predicted using the PASS web server which proved that that the complexes are more effective against fungal pathogens than bacterial pathogens. This preliminary theoretical study highlights β-CD’s potential as a carrier to enhance the therapeutic efficacy of antifungal drugs, addressing key challenges in treating fungal infections through improved solubility and bioavailability.