Structure-based virtual screening for potent inhibitors of GH-20 β-N-acetylglucosaminidase: Classical and machine...

GH-20 β-N-acetylglucosaminidases (GlcNAcases) are promising targets in the development of antimicrobial agents against Vibrio infections in humans and aquatic animals. In this study, we set up structure-based virtual screening to identify potential GH-20 GlcNAcase inhibitors from the Reaxys commercial database, using VhGlcNAcase from V. campbellii type strain ATCC® BAA 1116 as the protein target and Redoxal as the reference ligand. Using ChemPLP and RF-Score-VS machine learning scoring functions, eight lead compounds were identified and further evaluated for protein interaction preference and pharmacological properties. Protein-ligand analysis demonstrated that all selected compounds interacted exclusively at subsite - 1 with five hydrophobic residues W487, W505, W546, W582 and V544 at site S1, and with two polar residues, D437 and E438, at site 3. For subsite + 1, the most common residues were R274 and E584 at site 2 and I397 and Q398 at site 4. Based on the data obtained from binding free energy changes (ΔG°_binding), pharmacological property analysis and molecular dynamic simulations, two ChemPLP compounds, 338175 and 1146525, and one RF-Score-VS compound, 337447, were considered as the likely lead compounds. The most promising compound, 1146525, could serve as a scaffold for the future design of novel antimicrobial agents against Vibrio infections.