Structure-Based Rational Screening of Novel Hit Compounds with Structural Diversity for Cytochrome P450 Sterol 14α-Demethylase from Penicillium digitatum

Cytochrome P450 sterol 14α-demethylases (CYP51s) are essential enzymes in sterol biosynthesis and well-known as the target of antifungal drugs. All fungal CYP51s are integral membrane proteins, making structural and biophysical characterization more challenging. The X-ray crystallographic structure of CYP51 isolated from Mycobacterium tuberculosis (MT-CYP51) is the unique reported one hitherto. In the present study, a homology modeling three-dimensional structure of CYP51 from Penicillium digitatum (PD-CYP51) was generated by CPHmodels, in which the accuracy of sequence alignment could be improved by taking into account further structural conservation information, using MT-CYP51 as the template. Interaction mechanism between the active site of PD-CYP51 and its inhibitors were further investigated by molecular dynamics simulating and molecular docking. With the effective docking process and interaction analysis information, structure-based virtual screening was performed to pick out the thirty new potentia...