Development of hydroxamic acid derivatives as anticancer agent with the application of 3D-QSAR, docking and molecular dynamics simulations studies

The inhibition of histone deacetylase (HDAC) has become a well-recognized target for cancer therapy. Until now only five HDAC inhibitors i.e., SAHA, romidepsin (FK-228), belinostat, chidamide, and panobinostat have been approved by FDA. The first four of them are being employed for the treatment of cutaneous T-cell lymphoma and last one is being used for the treatment of multiple myeloma. In the present study, structure and ligand-based computational approaches were selected to design novel histone deacetylase inhibitors. A ligand-based pharmacophore model was developed employing phase module that exhibited five similar features and the generated pharmacophore models were validated by enrichment studies using the decoy set. Atom-based 3D-QSAR model was developed and validated using internal, partial least square (PLS) and external validation methods. The best 3D-QSAR model exhibited high value of regression coefficient for training set (R-2) = 0.926 and test (R-2) = 0.699, cross-validated coefficient (r(cv)(2)) = 0.967 and R-2 pred = 0.6578 with low root mean standard deviation (RMSE) = 0.4963. Additionally, the selected pharmacophore model (AAADR.12514) was employed as a 3D query for virtual screening against the ZINC database. The hit compounds were subsequently subjected to ligand-receptor interaction studies. Further, HDAC receptor-ligand complex were subjected to MM-GBSA and molecular dynamic simulation to evaluate the binding energy, strain energy, stability, and electrostatics of complex. Moreover, ADMET studies were also performed on resulted molecules. The outcome of these studies could be utilized for identification of novel lead for the development of HDAC inhibitors.