Isatin Derivatives as Human Intestinal Carboxylesterase Inhibitors: An Approach towards 3D-QSAR, Pharmacophore and Molecular Docking | Chapter 1 | Current Aspects in Pharmaceutical Research and Development Vol. 2

 Carboxylesterases (CEs) metabolise a variety of medications, and inhibiting them can increase the bioactivity or reduce the toxicity of substances activated by these enzymes. Isatin derivatives that were previously described as carboxylesterase inhibitors were chosen to develop a quantitative structure-activity link using k-nearest neighbour molecular field analysis (kNN MFA). The dataset consisted of 49 chemicals, and the data set was divided into training and test sets using the sphere exclusion (SE) technique. The models were created using various dissimilarity levels, and the best model (dissimilarity value 3.75) had a cross verified correlation coefficient (q2) of 0.8594 and a predicted correlation coefficient (pred r2) of 0.8106 with a test set of 9 chemicals. The QSAR models were built using the kNN-MFA methodology with stepwise (SW) forward-backward. The kNN-MFA contour plots revealed a link between the structural properties of substituted isatin derivatives and their actions, which could be exploited to develop novel CE inhibitors. Molsign and Pharmagist techniques demonstrate common two aromatic (AroC) and two hydrogen bond acceptors (HAc) properties in pharmacophore investigations. The results of this study could help with lead optimization and the development of potent carboxylesterase inhibitors. To discover probable interactions of the chemicals with the carboxylesterase active site, a molecular docking research was conducted. The pdb id 2hrq (crystal structure of human carboxylesterase with soman) was chosen for this purpose. Compound 62 has a similar docking score and binds to the enzyme's active site.

Author(s) Details

Sanmati K. Jain
Drug Discovery and Research Laboratory, SLT Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Bilaspur, 495009, India.

Piyush Ghode
Drug Discovery and Research Laboratory, SLT Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Bilaspur, 495009, India.

Achal Mishra
Faculty of Pharmaceutical Sciences, Shri Shankaracharya Group of Institutions, Junwani, Bhilai, India.

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