Title:QSAR Docking on Azoles as Inhibitors of Notum Carboxylesterase
Volume: 15
Issue: 3
Author(s): Amuthalakshmi Sivaperuman, Ramalakshmi Natarajan*, Manimegalai P, Arunkumar Subramani and Puratchikody Ayarivan
Affiliation:
- C.L. Baid Metha College of Pharmacy, Chennai,India
Keywords:
QSAR, MLR, carboxylesterase notum, validation, signalling, docking.
Abstract: Background: 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.
Objective: 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.
Methods: 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- manyout
(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.
Results: 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.
Conclusion: 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.
