Abstract
Sterol 14α-demethylases from Cytochrome P450 family (CYP51s) are essential enzymes in sterol biosynthesis and well-known as the target of antifungal drugs. The 3D structure of CYP51A from Penicillium italicum (PiCYP51A) was constructed through homology modeling based on the crystal structure of human CYP51A (PDB: 3LD6). Molecular dynamics (MD) simulation was operated to relax the initial model and followed by quality assessment using PROCHECK program. On the basis of the docking information on the currently available CYP51s with the patent demethylase inhibitors (DMIs), pharmacophore-based virtual screening combined with docking analysis was performed to pick out twelve new compounds from ZINC database. Six hits revealed in the ligand database suggested potential ability to inhibit PiCYP51A. Compared to patent fungicide triazolone, the top three lead compounds had similar or higher affinity with the target enzyme, and accordingly, exhibited comparable or lower EC50 values to P. italicum isolates. The results could provide references for de novo antifungal drug design.
Highlights
Citrus is the world’s most common crop grown in over 100 countries worldwide [1]
The human CYP51 has an identity of 37.66% on amino acid sequences with PiCYP51A, and is suitable to be the template for the homology modeling in this study
Synthetic fungicides based on cytochrome P450 target enzymes have been widely
Summary
Citrus is the world’s most common crop grown in over 100 countries worldwide [1]. The fungal diseases of blue mold on post-harvested citrus fruits, caused by Penicillium italicum, have led to30%–50% loss of annual citrus economy in China [2]. Citrus is the world’s most common crop grown in over 100 countries worldwide [1]. The fungal diseases of blue mold on post-harvested citrus fruits, caused by Penicillium italicum, have led to. Application of synthetic fungicides is the preferred method to control post-harvest diseases caused by fungal phytopathogens in fruits and vegetables. Sterol 14α-demethylases from Cytochrome P450 family (CYP51s) are essential enzymes in sterol biosynthesis and well-known as the target of antifungal drugs, which was membrane-bound and difficult to solve its crystal structure [3,4]. Demethylase inhibitors (DMIs) have been exploited as azole-antifungal drugs to inhibit lanosterol 14α-demethylase (CYP51), impairing ergosterol/lanosterol metabolisms and resulting in fungal growth inhibition [5]. It is imperative to design new and efficient fungicides for the treatment of pathogens of plants based on the CYP51 structure
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