3D-QSAR of histone deacetylase inhibitors as anticancer agents by genetic function approximation.

Histone deacetylases (HDACs) play a critical role in gene transcription and are implicated in cancer therapy and other diseases. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in the tumor cells. Although many such inhibitors have been designed and synthesized, but selective inhibitors for HDAC isoforms are lacking. Various hydroxamic acid analogues have been reported as HDAC inhibitors. Here, we report a three-dimensional quantitative structure-activity relationship (3D-QSAR) study performed using genetic function approximation (GFA) for this class of molecules. QSAR models were generated using a training set of 39 molecules and the predictive ability of final model was assessed using a test set of 17 molecules. The internal consistency of the final QSAR model was 0.712 and showed good external predictivity of 0.585. The results of the present QSAR study indicated that molecular shape analysis (MSA). thermodynamic and structural descriptors are important for inhibition of HDACs.