3D-QSAR and Molecular Docking Studies on Oxadiazole Substituted Benzimidazole Derivatives: Validation of Experimental Inhibitory Potencies Towards COX-2

Author(s): Vivek Asati, Piyush Ghode, Shalini Bajaj, Sanmati K. Jain, Sanjay K. Bharti*.

Journal Name: Current Computer-Aided Drug Design

Volume 15 , Issue 4 , 2019

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Abstract:

Background: In past few decades, computational chemistry has seen significant advancements in design and development of novel therapeutics. Benzimidazole derivatives showed promising anti-inflammatory activity through the inhibition of COX-2 enzyme.

Objective: The structural features necessary for COX-2 inhibitory activity for a series of oxadiazole substituted benzimidazoles were explored through 3D-QSAR, combinatorial library generation (Combi Lab) and molecular docking.

Methods: 3D-QSAR (using kNN-MFA (SW-FB) and PLSR (GA) methods) and Combi Lab studies were performed by using VLife MDS Molecular Design Suite. The molecular docking study was performed by using AutoDockVina.

Results: Significant QSAR models generated by PLSR exhibited r2 = 0.79, q2 = 0.68 and pred_r2 = 0. 84 values whereas kNN showed q2 = 0.71 and pred_r2 = 0.84. External validation of developed models by various parameters assures their reliability and predictive efficacy. A library of 72 compounds was generated by combinatorial technique in which 11 compounds (A1-A5 and B1-B6) showed better predicted biological activity than the most active compound 27 (pIC50 = 7.22) from the dataset. These compounds showed proximal interaction with amino acid residues like TYR355 and/or ARG120 on COX-2(PDB ID: 4RS0).

Conclusion: The present work resulted in the design of more potent benzimidazoles as COX-2 inhibitors with good interaction as compared to reference ligand. The results of the study may be helpful in the development of novel COX-2 inhibitors for inflammatory disorders.

Keywords: 3D-QSAR, k-nearest neighbor, Lipinski’s rule of five, virtual screening, COX-2, benzimidazole derivatives.

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Article Details

VOLUME: 15
ISSUE: 4
Year: 2019
Page: [277 - 293]
Pages: 17
DOI: 10.2174/1573409914666181003153249
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