2D-Qsar and molecular docking studies of hydroxamic acid derivatives bearing benzimidazole scaffold as histone deacetylase 6 inhibitors

In this study, 2D-QSAR analysis and molecular docking were performed to investigate the relationship between the hydroxamate-based HDAC inhibitors with benzimidazole scaffold and the activity toward HDAC6. A dataset of 55 N-hydroxybenzamide, N-hydroxypropenamide derivatives containing benzimidazole structure with HDAC6 in vitro activity were collected. The MLR (multiple linear regression) method was used to build a 2D-QSAR model when internal (leave-one-out cross validation) and external validation were also tested. In addition, the molecular docking study was performed by using MOE 2008 software to validate the affinity of the inhibitors at the active site of HDAC6 enzyme (PDB ID: 5EEN). The model was developed using 7 molecular descriptors from 55 compounds with results of R2 = 0.905, RMSE = 0.343 and the concordance correlation coefficient (CCC) = 0.950. The molecular docking results also demonstrated the favorable binding interactions of compounds into the active site on the structure of HDAC6 and the essential residues in the pocket and the key interactions of benzimidazole ring with these residues. Notably, the study enables a reliable model to predict the inhibition activity of new benzimidazole-containing inhibitors in HDAC6.