INTEGRATING STRUCTURE AND LIGAND-BASED APPROACHES FOR MODELLING THE HISTONE DEACETYLASE INHIBITION ACTIVITY OF HYDROXAMIC ACID DERIVATIVES

Objective: Structure and ligand-based drug design approaches have be been integrated to accurately predict the inhibition activity of hydroxamic acid (HA) derivatives against the histone deacetylase-2 enzyme (HDAC2). Methods: The “active conformations” of the ligands in the binding site of the enzyme were determined by docking assays. More than 1000 0–3 dimensional molecular descriptors included in Dragon package were calculated and utilized for developing quantitative structure-activity relationship (QSAR) models through a multiple linear regression approach coupled with the genetic algorithm (GA-MLR). Results: The final model obtained showed suitable robustness and stability, with low correlation between descriptors and good predictive power. QSAR model was then used for screening bioactivity from a series of 36 novel HAs and found five candidates with very good bioactivity (half maximal inhibitory concentrationu003c0.1 μM). Docking experiment revealed the binding mode of these compounds into the active site of HDAC2. Drug-likeness and toxicity profiles of the compounds were checked through chemoinformatics tools. Conclusion: The results from this study can lead to rational design and synthesis of highly selective and potent HDAC2 inhibitors.