QSAR Docking on Azoles as inhibitors of Notum carboxylesterase

Abstract

Carboxylesterase Notum is a negative regulator of Wnt signaling. Notum carboxylesterase is a carboxylic ester hydrolase enzyme that functions as a negative feedback regulator of Wnt proteins by depalmitoylation reaction. It is of great importance to understand the pathway of Wnt regulation because, conversely, misregulation of Wnt signaling is a telltale sign of cancer and other degenerative diseases. The Wnt inhibition is important in the control of colorectal cancer. In the present study, we carried out a QSAR analysis of a series of reported compounds with carboxylesterase Notum inhibitory activity using multiple regression analysis. A series of 83 compound datasets of pyrrole derivatives with carboxy Notum inhibitory values were taken from the reported literature. The study was performed by conducting multiple linear regression analysis followed by validation of the model. The multiple linear regression (MLR) models with the highest coefficients of correlation (R2) and explained variance in leave-one-out (Q2 LOO) prediction and leave-many-out (Q2 LMO) were selected for the whole dataset. The developed models were subjected to internal and external validation. The reliability of the predicted model was checked by plotting the Williams plot. The docking methodology was performed using Autodock 4 for the designed compounds to study the interaction between the ligand and the receptor. The best model generated exhibited an r2 value of 0.7413, Q2LOO =0.6379, Q2LMO =0.6368. Novel compounds of phenyl pyrrolidine were designed based on generated QSAR equations. The carboxylesterase Notum inhibitory activity was predicted using the QSAR equations. The docking studies were carried out for designed compounds using Autodock against Carboxylesterase Notum esterase. From the results, the designed compounds were found to inhibit Notum Carboxylase. Thus, the study led to the development of a novel lead compound for Carboxylesterase Notum.