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.
New benzimidazole derivatives as inhibitors of Pteridine reductase 1: Design, molecular docking study and ADMET prediction
