title: Pharmacophore modeling, 3D-QSAR and DFT studies of IWR small-molecule inhibitors of Wnt response.
abstract: In this study, a 5-point pharmacophore model was developed and the model was used to generate a predictive atom-based 3D quantitative structure activity relationship (3D-QSAR) analysis for the studied dataset of 50 compounds. The obtained 3D-QSAR model shows correlation coefficient (R(2)) of 0.87 for training set compounds and excellent predictive power (Q(2)) of 0.81 for cross-validated test set compounds. External validation indicated that our 3D-QSAR model has high predictive power with [Formula: see text] and [Formula: see text] values of 0.99 and 0.65, respectively. The most active and least active compounds were further optimized using density functional theory at B3LYP/3-21*G level. Further, pharmacophoric model was employed for pharmacophore-based screening to identify potential inhibitors against Wnt/β-catenin pathway. Hence, these molecules could act as selective inhibitors of Wnt/β-catenin pathway which can be experimentally validated. The backbone of these inhibitors could serve as templates for designing drug-like molecules specifically targeting Wnt/β-catenin pathway.
authors.affiliation: Department of Bioinformatics, Science Block, Alagappa University , Karaikudi, Tamil Nadu , India.
authors.forename: Palani
authors.initials: P
authors.lastname: Kirubakaran
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Karthikeyan
mesh_terms: D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D054852:Small Molecule Libraries; D051153:Wnt Proteins; D051176:beta Catenin