The binding mechanism between azoles and FgCYP51B, sterol 14α‐demethylase of Fusarium graminearum

BACKGROUND: Fusarium graminearum is the main pathogen of Fusarium head blight (FHB), a worldwide plant disease and a major disease of wheat in China. Control of FHB is mainly dependent on the application of demethylase inhibitor (DMI) fungicides. Fungal sterol 14α‐demethylase enzymes (CYP51) are the main target for DMI fungicides. A molecular modeling study and biological evaluation were performed to investigate the binding mechanism between azoles and CYP51B in F. graminearum. RESULTS: A homology model based on the crystal structure of Aspergillus fumigatus was built. Molecular docking and molecular dynamics (MD) simulations were then used to identify the optimum binding mode of propiconazole (PRP), diniconazole (DIN), triadimenol (TRL), tebuconazole (TEC) and triadimefon (TRN) with FgCYP51B. Furthermore, the binding free energy of the five protein–inhibitor complexes was calculated using molecular mechanics generalized Born surface area and Poisson–Boltzmann surface area (MM‐GB/PBSA) methods. Key residues in the selective binding of azoles to FgCYP51B were recognized by per‐residue free energy decomposition analysis. The five ligands have a similar binding mode in the active pocket. The binding free energy to the enzyme for inhibitors PRP and TEC is more favorable than that of TRN, TRL and DIN. Furthermore, the amino acid residues Phe511, Val136, Ile374, Ala308, Ser312 and Try137 of FgCYP51B are key residues interacting with azoles fungicides. From the experimental evaluation, the 50% effective concentration (EC₅₀) values for PRP, TEC, DIN, TRL and TRN are 0.024, 0.047, 0.148, 0.154 and 0.474 mg L–¹, respectively. These five molecules exhibit potential inhibitory activity against CYP51B protein from F. graminearum. CONCLUSION: Azole fungicides for FgCYP51B should possess more hydrophobic groups interacting with residues Phe511, Val136, Ile374, Ala308, Ser312 and Tyr137. PRP and TEC are preferable for the control of FHB than DIN, TRL and TRN. © 2017 Society of Chemical Industry