3-D QSAR studies on histone deacetylase inhibitors. A GOLPE/GRID approach on different series of compounds

Docking simulation and three-dimensional quantitative structure-activity relationships (3D-QSARs) analyses were conducted on four series of HDAC inhibitors. The studies were performed using the GRID/GOLPE combination using structure-based alignment. Twelve 3-D QSAR models were derived and discussed. Compared to previous studies on similar inhibitors, the present 3-D QSAR investigation proved to be of higher statistical value, displaying for the best global model r(2), q(2), and cross-validated SDEP values of 0.94, 0.83, and 0.41, respectively. A comparison of the 3-D QSAR maps with the structural features of the binding site showed good correlation. The results of 3D-QSAR and docking studies validated each other and provided insight into the structural requirements for anti-HDAC activity. To our knowledge this is the first 3-D QSAR application on a broad molecular diversity training set of HDACIs.