Structural insights on identification of potential lead compounds targeting WbpP inVibrio vulnificusthrough structure-based approaches

Abstract

WbpP encoding UDP-GlcNAC C4 epimerase is responsible for the activation of virulence factor in marine pathogen Vibrio vulnificus (V. vulnificus) and it is linked to many aquatic diseases, thus making it a potential therapeutic target. There are few reported compounds that include several natural products and synthetic compounds targeting Vibrio sp, but specific inhibitor targeting WbpP are unavailable. Here, we performed structure-based virtual screening using chemical libraries such as Binding, TOSLab and Maybridge to identify small molecule inhibitors of WbpP with better drug-like properties. Deficient structural information forced to model the structure and the stable protein structure was obtained through 30 ns of MD simulations. Druggability regions are focused for new lead compounds and our screening protocol provides fast docking of entire small molecule library with screening criteria of ADME/Lipinski filter/Docking followed by re-docking of top hits using a method that incorporates both ligand and protein flexibility. Docking conformations of lead molecules interface displays strong H-bond interactions with the key residues Gly101, Ser102, Val195, Tyr165, Arg298, Val209, Ser142, Arg233 and Gln200. Subsequently, the top-ranking compounds were prioritized using the molecular dynamics simulation-based conformation and stability studies. Our study suggests that the proposed compounds may aid as a starting point for the rational design of novel therapeutic agents.

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

“…The model has ≥90% of the amino acid residues present in allowed regions represents a good quality model. Similar protocols were followed as reported recently in drug discovery process and lead identification [66][67][68]. The UBE2D4 model has 91.9% of the amino acid residues present in the allowed regions, and hence, it is a good quality model.…”

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

“…Sasikala et al also conducted a virtual screen of RmlC and identified several potential inhibitors of the Vibrio vulnificus enzyme (also known as WbpP). 261 However, none of these compounds were confirmed as hits in biochemical or biophysical screens.…”

“…[258][259][260] RmlC is also responsible for activation of the virulence factor in the marine pathogen Vibrio vulnificus. 261 Several inhibitors of RmlC have been previously characterised (including the high-throughput screening inhibitors noted above; 228 vide supra, Fig. 16), although many have limited aqueous solubility.…”

“… 258–260 RmlC is also responsible for activation of the virulence factor in the marine pathogen Vibrio vulnificus . 261 …”

Anti-vibriosis bioactive molecules from Arctic Penicillium sp. Z2230

“…Three-dimensional (3D) crystal structures or homology models of the Vibrio-speci c targets reported in recent years on RCSB Protein Data Bank (PDB) or UniProt Database were used for molecular docking (Bonardi et Sasikala et al 2016). The AutoDock Tools 1.5.6 software was used to remove the water molecules, add the nonpolar hydrogen, and calculate the Gasteiger charges for the protein structures.…”