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Development and Validation of a Robust QSAR Model for Benzothiazole Hydrazone Derivatives as Bcl-XL Inhibitors

[ Vol. 16 , Issue. 1 ]

Author(s):

Pawan Gupta* and Aleksandrs Gutcaits   Pages 11 - 20 ( 10 )

Abstract:


Background: B-cell Lymphoma Extra Large (Bcl-XL) belongs to B-cell Lymphoma two (Bcl-2) family. Due to its over-expression and anti-apoptotic role in many cancers, it has been proven to be a more biologically relevant therapeutic target in anti-cancer therapy. In this study, a Quantitative Structure Activity Relationship (QSAR) modeling was performed to establish the link between structural properties and inhibitory potency of benzothiazole hydrazone derivatives against Bcl-XL.

Methods: The 53 benzothiazole hydrazone derivatives have been used for model development using genetic algorithm and multiple linear regression methods. The data set is divided into training and test set using Kennard-Stone based algorithm. The best QSAR model has been selected with statistically significant r2 = 0.931, F-test =55.488 RMSE = 0.441 and Q2 0.900.

Results: The model has been tested successfully for external validation (r2 pred = 0.752), as well as different criteria for acceptable model predictability. Furthermore, analysis of the applicability domain has been carried out to evaluate the prediction reliability of external set molecules. The developed QSAR model has revealed that nThiazoles, nROH, EEig13d, WA, BEHv6, HATS6m, RDF035u and IC4 descriptors are important physico-chemical properties for determining the inhibitory activity of these molecules.

Conclusion: The developed QSAR model is stable for this chemical series, indicating that test set molecules represent the training dataset. The model is statistically reliable with good predictability. The obtained descriptors reflect important structural features required for activity against Bcl-XL. These properties are designated by topology, shape, size, geometry, substitution information of the molecules (nThiazoles and nROH) and electronic properties. In a nutshell, these characteristics can be successfully utilized for designing and screening of novel inhibitors.

Keywords:

Bcl-XL, descriptors, MLR, genetic algorithm, QSAR model, validation, domain of applicability analysis.

Affiliation:

CNS Active Compound Laboratory, Latvian Institute of Organic Synthesis, Riga, LV1006, CNS Active Compound Laboratory, Latvian Institute of Organic Synthesis, Riga, LV1006

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