Structure-based virtual screening and ADME/T-based prediction analysis for the discovery of novel antifungal CYP51 inhibitors

Abstract

With the increasing incidence of pathogenic fungi and drug-resistant fungi in clinic, it has become very important to develop the novel rate-limiting enzyme 14α-demethylase (CYP51) as an antifungal inhibitor. In this study, a method involving structure-based virtual screening was employed. First, a publicly available database was obtained from the Dow Chemical Company, and the database was screened by the designed pharmacophore model of CYP51 inhibitors. Then, the pharmacophore search hits were docked into the CYP51 crystal structure. Finally, sixteen compounds were selected for antifungal inhibition assay, and most of the compounds showed a certain degree of antifungal activity. In particular, compounds, , and exhibited significant antifungal and anti-drug resistance activities by blocking the synthesis of ergosterol. The molecular docking and ADME/T properties of the compounds ,, and were further predicted, and the results indicated that they can form hydrophobic and coordination interactions with the active sites of CYP51. At the same time, compounds and showed promising drug-like properties. This study reveals that the compounds can be further optimized and developed as lead compounds.

Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors

“…1). [25][26][27] For the most potent inhibitors (compounds 1, 2, 3, and 7), the principal and MaxOmitFeat values were endued with 2 and 0, respectively. For the moderate inhibitors (compounds 4, 5, and 6), the principal and Max-OmitFeat values were both set to 1.…”

Multifunctional in vitro, in silico and DFT analyses on antimicrobial BagremycinA biosynthesized by Micromonospora chokoriensis CR3 from Hieracium canadense

“…The antimicrobial and antifungal mechanisms of BagA were investigated by retrieving the 3D crystal structures of Candida albicans sterol 14-α demethylase (CaCYP51) (PDB ID: 5TZ1) 34 and Staphylococcus aureus thymidylate kinase (SaTMK) (PDB ID: 4QGG) 35 from the PDB database. For the comparison study, their human orthologs (hCYP51 and hTMK) were also retrieved with PDB IDs of 3JUV and 1E2Q, respectively.…”

Antifungal screening and in silico mechanistic studies of an in‐house azole library

“…Recent studies have taken advantage of property-based, ligand-based, and structure-based methods, or their combinations, to identify and optimize fungal CYP51 azole inhibitors (Dogan et al, 2017;Sun, Huang, & Liu, 2017;Sun, Zhang, Liu, Hou, & Liu, 2018;Thamban Chandrika et al, 2018;Wu et al, 2018;Yates, Garvey, Shaver, Schotzinger, & Hoekstra, 2017). In these studies, not only several antifungal hits were identified but some key residues for the enzyme inhibition were also determined in reference to biological studies.…”