Targeting CYP51 for drug design by the contributions of molecular modeling

Abstract

CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles.

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

“…Residues Tyr123, Ala136, Met301, Ala308 and Ile374 plus Phe511, and Tyr123, Tyr137, Phe230, Ile377 plus Phe511 were recognized in Cypb–TRL and Cypb–DIN complexes, respectively. Previously, other molecular docking studies have shown that triazole derivatives contact the CYP51 family mainly through non‐bound interactions, such as hydrophobic, van der Waals and aromatic stacking interactions . Our results analyzing the binding mode of FgCYP51–inhibitors complexes are in agreement.…”

“…Previously, other molecular docking studies have shown that triazole derivatives contact the CYP51 family mainly through non-bound interactions, such as hydrophobic, van der Waals and aromatic stacking interactions . 37,38 Our results analyzing the binding mode of FgCYP51-inhibitors complexes are in agreement.…”

Molecular electrostatic potential mapping for PANI emeraldine salts and PANI@Ag core-shell

“…By molecular modeling one could explain several chemical, Physical and biological processes related to the 3D structure of the molecule. In that sense molecular modeling or molecular simulation became an important tool for studying the physical, biological and chemical behavior of the under investigation molecular system [13][14][15][16][17][18]. By means of molecular modeling one can calculate several parameters like the bond angle, bond length, the vibrational spectra [19], electronic transitions and the electrostatic potential [20,21] around the studied molecule.…”

Uptake and efflux kinetics, and intracellular activity of voriconazole against Aspergillus fumigatus in human pulmonary epithelial cells: a new application for the prophylaxis and early treatment of invasive pulmonary aspergillosis

“…Voriconazole belongs to triazole and exhibits broad‐spectrum antifungal activity against Aspergillus , fluconazole‐resistant Candida , Fusarium and Scedosporium species , making it effective in preventing and treating invasive fungal infections in immunocompromised patients. As a result, it emerged as the preferred prophylactic agent in lung transplant recipients .…”