Discovery of Chitin Deacetylase Inhibitors through Structure-Based Virtual Screening and Biological Assays

Abstract

Chitin deacetylase (CDA) inhibitors were developed as novel antifungal agents because CDA participates in critical fungal physiological and metabolic processes and increases virulence in soilborne fungal pathogens. However, few CDA inhibitors have been reported. In this study, 150 candidate CDA inhibitors were selected from the commercial Chemdiv compound library through structure-based virtual screening. The top-ranked 25 compounds were further evaluated for biological activity. The compound J075-4187 had an IC50 of 4.24 ± 0.16 μM for AnCDA. Molecular docking calculations predicted that compound J075-4187 binds to the amino acid residues, including active sites (H101, D48). Furthermore, compound J075-4187 inhibited food spoilage fungi and plant pathogenic fungi, with minimum inhibitory concentration (MIC) at 260 μg/ml and minimum fungicidal concentration (MFC) at 520 μg/ml. Therefore, compound J075-4187 is a good candidate for use in developing antifungal agents for fungi control.

Combined Application of Tacrolimus with Cyproconazole, Hymexazol and Novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines as Antifungals: In Vitro Growth Inhibition and In Silico Molecular Docking Analysis to Fungal Chitin Deacetylase

“…In addition, the effective dosages of the substances may be even further decreased upon additional investigation. According to the calculated molecular docking, triazole 5 has a high affinity for AngCDA and AnCDA , which is stronger than those reported for chitotriose [ 66 ], polyoxorin D [ 41 , 42 ], and J075-4187 [ 40 ]. An expansion of the concentration ranges, especially for tacrolimus, might reveal additional synergistic activities, which allow the use of combinations of more eco-friendly antifungals at lower concentrations, with the same effectiveness.…”

“…The active site of An CDA, and in a similar configuration to AngC DA, includes the HIS-HIS-ASP metal-binding triad (HIS97, HIS101, and ASP48), a catalytic acid (HIS196, aiding sugar departure), and a catalytic acid (ASP47) [ 40 ]. CDAs of Colletotrichum sp.…”

“…CDAs of Colletotrichum sp. [ 67 ] and A. niger [ 40 ], certain carboxylic acids, such as EDTA, ultimately fit into this structure. Therefore, EDTA binds to Ang CDA via four hydrogen bonds that involve HIS97, TYR138, TYR166, and HIS199.…”

“…Macromolecules from the Protein Data Bank (PDB) were used as the biological targets, namely, A. niger CDA ( Ang CDA; PDB ID: 7BLY) [ 43 ] and A. nidulans CDA ( An CDA; PDB ID: 2Y8U) [ 44 ]. Polyoxorin D [ 42 ] and J075-4187 (2-chloro- N -((5-( p -tolyl)-1,2,4-oxadiazol-3-yl)methyl)nicotinamide) [ 40 ] were chosen as the references. The seven mol files of tacrolimus ( 1 ), hymexazol ( 2 ), cyproconazole ( 3 ), triazoles ( 4) , and ( 5) , polyoxorin D ( 6 ), J075-4187 ( 7 ) ( Figure 1 ) were drawn by ChemDraw Professional 15.0 and optimized by HyperChem 8.0.8; mol files were converted to pdb by Open Babel GUI 2.3.2; pdb files were converted to pdbqt by AutoDocTools 1.5.6.…”

“…asoensis , was registered as an official antifungal agrochemical and chitin synthase inhibitor (EC 2.4.1.16) [ 39 ]. In addition, among 3000 small molecular weight substances, Compound J075-4187 ( Figure 1 ) showed the highest inhibitory activity of 83.77% toward A. niger CDA (IC 50 of 4.24 ± 0.16 μM) [ 40 ]. Thus, according to their structural similarity to the studied substances, polyoxorin D [ 41 , 42 ] and J075-4187 [ 40 ] were chosen as the comparative standards of affinity toward chitin deacetylases Ang CDA from A. niger (protein data bank (PDB) ID: 7BLY) [ 43 ] and An CDA from A. nidulans (PDB ID: 2Y8U) [ 44 ].…”