Structural Modeling of CYP51 from Penicillium digitatum and the Inhibitor Coordination Interactions

Penicillium digitatum Sterol 14α-demethylase (PdCYP51), a prime enzyme in membrance sterol biosynthesis, is a key target of antifungal drugs for citrus disease. Based on the recently determined X-ray crystal structure human CYP51, a three-dimensional structure model of PdCYP51 was built through homology modeling. After molecular dynamics (MD) simulation, the refined model was assessed by Verify-3D and Procheck, which confirmed that the refined model was reliable. Further evaluation on the model quality was performed by investigating the interaction of some sterol 14α-demethylase inhibitors (DMIs) with the modeled enzyme. Molecular docking program was employed to determine such interactions. The binding pattern predicted by the docking revealed that DMI inhibitor interacted with PdCYP51 mainly through hydrogen-bonding and hydrophobic interactions. Moreover, the results are compatible with the spectra assay data in the laboratory. The docking complex provided further refinement of the DMI binding interaction that may be used as a basis for virtual screening and for novel design to discover more potent compounds.