Exploration of the binding of antifungal drugs to human P450 2C9 based on docking and molecular dynamics simulation.

Azole compounds, commonly used antifungal agents for the treatment of systemic fungal infections, have been confirmed to show inhibition to some P450 enzymes. However, the potential inhibition or interaction mechanism is elusive. Here, the detailed interaction between first‐generation antifungal agents (miconazole, and its derivatives fluconazole and voriconazole) and CYP2C9 are studied using docking and molecular dynamics (MD) simulation methods. Docking results show that azoles are mainly located in the cavity formed by helices A, F, I, and heme group. MD results indicate flu‐1 and vor‐2 undergo large conformational changes mediated by inter/intramolecular hydrogen bonds (H‐bonds), while other azole conformations exhibit low flexibility in the active site. Interestingly, one water (W7255) joins the interaction between flu‐1 and N204, implying the significance of water in regulating the binding of fluconazole. MM‐GBSA analysis manifests that miconazole possesses highest binding affinity compared to fluconazole and voriconazole, which agrees well with previous reports. Moreover, the per‐residue decomposition suggests that the favorable interactions are dominated by ΔGvdW and ΔGnonpl between azoles and residues (V113/F114, I205/L208, A297/E300/T301, F476/A477) and ΔGvdW should be further ascribed to CH⋯Cl, CH⋯N, CH⋯O and CH⋯π interactions. [ABSTRACT FROM AUTHOR]