3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment

Histone deacetylases (HDACs) enzyme is a promising target for the development of anticancer drugs. The enzyme-bound conformation of Trichostatin A (TSA) (PDB ID:1C3R) as an inhibitor of HDACs was used to manually construct a pharmacophore model. This model was then successfully used to identify the bioactive conformation and align flexible and structurally diverse molecules. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on hydroxamate-based HDACs inhibitors based on phamacophore alignment. The best predictions were obtained with CoMFA standard model (q2 = 0.726, r2 = 0.998) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q2 = 0.610, r2 = 0.995). Both of the models were validated by an external test set, which gave a satisfactory predictive r2 value of 0.800 and 0.732, respectively. Graphical interpretation of the results revealed important structural features of the inhibitors related to the active site of HDACs. The results may be exploited for further design and virtual screening for some novel HDACs inhibitors.

A chemical feature-based pharmacophore model was manually constructed based on the bound conformation of TSA as a potent HDACs inhibitor. This pharmacophore model was used to identify the bioactive conformations, and to align the structurally diverse hydroxamate-based compounds. Two highly predictive and statistically significant CoMFA and CoMSIA models were derived from pharmacophore-based alignment.Figure optionsDownload as PowerPoint slide