Pharmacophore modeling, 3D-QSAR and DFT studies of IWR small-molecule inhibitors of Wnt response

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 r(0)(2) and r(m)(2) 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/beta-catenin pathway. Hence, these molecules could act as selective inhibitors of Wnt/beta-catenin pathway which can be experimentally validated. The backbone of these inhibitors could serve as templates for designing drug-like molecules specifically targeting Wnt/beta-catenin pathway.