Studies on the optimization of metzincins inhibitors by using docking

Abstract

A series of non-peptidic inhibitors of FTase based on the m-aminobezoic acid spacer were designed and optimized low nano molar inhibitors were identified that was presumed to utilize hydrophobic binding interaction near the isoprene part of bound FPP in the enzyme. We became to have the question about the existence of bisubstrate inhibitor and the results from this study told us that it was a difficult task to design such substrate. Gelastatins showed potent inhibitory activity against TACE and MMPs, but they were thermally unstable and showed low selectivity against other metalloproteinases. To overcome these drawbacks of gelastatins, we designed coumarine moiety. Coumarine showed TACE and MMP-2 inhibition but more active to TACE. The difference between the inhibitory activity of TACE and MMP-2 with gelastatine explained that whether polyene group of gelastatine insert into P1’Pocket or not. Docking simulation and 3-D quantitative structure activity relationship analysis were conducted on a series of the potent lactam based HDAC inhibitors. Optimal conformation of the inhibitors was obtained from docking model in the active site of HDLP by using Insight II. The descriptors were examined for QSAR study by using Cerius 2. Finally, 6 descriptors were chosen as the independent variables for the generation of QSAR equation (training set : $r^2$ = 0.77, test set : $r^2$ = 0.76). QSAR results will be helpful in the further design of novel HDAC inhibitor.