title: Structural dynamics and inhibitor searching for Wnt-4 protein using comparative computational studies.
abstract: Wnt-4 (wingless mouse mammary tumor virus integration site-4) protein is involved in many crucial embryonic pathways regulating essential processes. Aberrant Wnt-4 activity causes various anomalies leading to gastric, colon, or breast cancer. Wnt-4 is a conserved protein in structure and sequence. All Wnt proteins contain an unusual fold comprising of a thumb (or N-terminal domain) and index finger (or C-terminal domain) bifurcated by a palm domain. The aim of this study was to identify the best inhibitors of Wnt-4 that not only interact with Wnt-4 protein but also with the covalently bound acyl group to inhibit aberrant Wnt-4 activity. A systematic computational approach was used to analyze inhibition of Wnt-4. Palmitoleic acid was docked into Wnt-4 protein, followed by ligand-based virtual screening of nearly 209,847 compounds; conformer generation of 271 compounds resulted from extensive virtual screening and comparative docking of 10,531 conformers of 271 unique compounds through GOLD (Genetic Optimization for Ligand Docking), AutoDock-Vina, and FRED (Fast Rigid Exhaustive Docking) was subsequently performed. Linux scripts was used to handle the libraries of compounds. The best compounds were selected on the basis of having maximum interactions to protein with bound palmitoleic acid. These represented lead inhibitors in further experiments. Palmitoleic acid is important for efficient Wnt activity, but aberrant Wnt-4 expression can be inhibited by designing inhibitors interacting with both protein and palmitoleic acid.
authors.affiliation: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Mirza A
authors.initials: MA
authors.lastname: Hammad
authors.affiliation: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Syed Sikander
authors.initials: SS
authors.lastname: Azam
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D030562:Databases, Protein; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D012984:Software; D060528:Wnt4 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D005229:Fatty Acids, Monounsaturated; D008024:Ligands; D060528:Wnt4 Protein; C008757:palmitoleic acid
keywords: cancer; comparative study; inhibitor searching; molecular docking; natural products; thumb-index fold; virtual screening