Quantitative structure-activity relationships (QSAR) of 65 different molecular series histone deacetylase inhibitors (HDACIs) with only one common pyrrole ring were studied by using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and hologram quantitative structure-activity relationship (HQSAR). The leave-one-out cross-validation q2 values of CoMFA, CoMSIA and HQSAR models were 0.623, 0.662 and 0.716, and non-cross-validated r2 values were 0.952, 0.909 and 0.891, respectively. The contour maps and atom contribution map provided helpful visualization information for structural modification of the HDACIs for better activity. A further docking study was carried out by using Surflex-dock method. Sixty-five compounds were docked into histone deacetylase (PDB ID 1T64). A reasonable docking model between inhibitors and the protein was obtained. The interaction between ligands and the receptor can reveal the binding mode of the HDAC inhibitors and HDAC enzyme. According to QSAR and docking results, eight new molecules were proposed, and their activities were predicted by using the established QSAR model and docking method. The results indicated that the proposed potential molecules have a potent activity.
Keywords: CoMFA, CoMSIA, HQSAR, HDACIs, Surflex-dock