A novel approach for the identification of selective anticonvulsants based on differential molecular properties for TBPS displacement and anticonvulsant activity: An integrated QSAR modelling

Savita Bhutoria, Nanda Ghoshal

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

In order to gain insight into the structural and molecular requirements influencing the anticonvulsant activity against Pentylenctetrazole (PTZ)-induced seizures and [35S] tert- Butyl-bicyclophosphorothionate (TBPS) displacement property (a measure of binding to GABAA receptor), Quantitative Structure-Activity Relationship (QSAR) studies have been performed on a series of congeneric anticonvulsant agents proposed to act by binding to the lactone site of the GABAA receptor. The aim of this work was to identify and analyse the various functionalities, which determine the TBPS displacement property and anticonvulsant activity by correlating with various molecular descriptors. Statistical techniques like Principal Component Analysis (PCA), Partial Least Squares (PLS), Multiple Linear Regression (MLR) and Genetic Function Approximation (GFA) were applied to identify the structural and physicochemical requirements for TBPS displacement property and anticonvulsant activity. The generated equations were statistically validated using leave-one-out cross-validation technique and randomization. The best models were also validated by prediction of activity of compounds, not used for the development of QSAR models. The results from reasonably good QSAR models (statistically validated) clearly indicated that TBPS displacement property and the anticonvulsant activity are defined by different molecular parameters. Based on this finding, a novel approach is proposed, using integrated QSAR modelling, for the identification of potential and selective anticonvulsant agents.

Original languageEnglish (US)
Pages (from-to)876-889
Number of pages14
JournalQSAR and Combinatorial Science
Volume27
Issue number7
DOIs
StatePublished - Jul 2008
Externally publishedYes

Fingerprint

Quantitative Structure-Activity Relationship
Anticonvulsants
GABA-A Receptors
Linear regression
Principal component analysis
Lactones
Random Allocation
Principal Component Analysis
Least-Squares Analysis
Linear Models
Seizures

Keywords

  • Anticonvulsants
  • GABA
  • Picrotoxin
  • QSAR
  • TBPS

ASJC Scopus subject areas

  • Organic Chemistry
  • Computer Science Applications
  • Drug Discovery

Cite this

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abstract = "In order to gain insight into the structural and molecular requirements influencing the anticonvulsant activity against Pentylenctetrazole (PTZ)-induced seizures and [35S] tert- Butyl-bicyclophosphorothionate (TBPS) displacement property (a measure of binding to GABAA receptor), Quantitative Structure-Activity Relationship (QSAR) studies have been performed on a series of congeneric anticonvulsant agents proposed to act by binding to the lactone site of the GABAA receptor. The aim of this work was to identify and analyse the various functionalities, which determine the TBPS displacement property and anticonvulsant activity by correlating with various molecular descriptors. Statistical techniques like Principal Component Analysis (PCA), Partial Least Squares (PLS), Multiple Linear Regression (MLR) and Genetic Function Approximation (GFA) were applied to identify the structural and physicochemical requirements for TBPS displacement property and anticonvulsant activity. The generated equations were statistically validated using leave-one-out cross-validation technique and randomization. The best models were also validated by prediction of activity of compounds, not used for the development of QSAR models. The results from reasonably good QSAR models (statistically validated) clearly indicated that TBPS displacement property and the anticonvulsant activity are defined by different molecular parameters. Based on this finding, a novel approach is proposed, using integrated QSAR modelling, for the identification of potential and selective anticonvulsant agents.",
keywords = "Anticonvulsants, GABA, Picrotoxin, QSAR, TBPS",
author = "Savita Bhutoria and Nanda Ghoshal",
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T1 - A novel approach for the identification of selective anticonvulsants based on differential molecular properties for TBPS displacement and anticonvulsant activity

T2 - An integrated QSAR modelling

AU - Bhutoria, Savita

AU - Ghoshal, Nanda

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AB - In order to gain insight into the structural and molecular requirements influencing the anticonvulsant activity against Pentylenctetrazole (PTZ)-induced seizures and [35S] tert- Butyl-bicyclophosphorothionate (TBPS) displacement property (a measure of binding to GABAA receptor), Quantitative Structure-Activity Relationship (QSAR) studies have been performed on a series of congeneric anticonvulsant agents proposed to act by binding to the lactone site of the GABAA receptor. The aim of this work was to identify and analyse the various functionalities, which determine the TBPS displacement property and anticonvulsant activity by correlating with various molecular descriptors. Statistical techniques like Principal Component Analysis (PCA), Partial Least Squares (PLS), Multiple Linear Regression (MLR) and Genetic Function Approximation (GFA) were applied to identify the structural and physicochemical requirements for TBPS displacement property and anticonvulsant activity. The generated equations were statistically validated using leave-one-out cross-validation technique and randomization. The best models were also validated by prediction of activity of compounds, not used for the development of QSAR models. The results from reasonably good QSAR models (statistically validated) clearly indicated that TBPS displacement property and the anticonvulsant activity are defined by different molecular parameters. Based on this finding, a novel approach is proposed, using integrated QSAR modelling, for the identification of potential and selective anticonvulsant agents.

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