Design and synthesis of matrix metalloproteinase inhibitors guided by molecular modeling. Picking the S-1 pocket using conformationally constrained inhibitors

Conformationally constrained MMP inhibitors based on a D-proline scaffold w ere designed using AutoDock as a modeling program. Thus a family of D-proli ne hydroxamic acids, having differentiated functionality at the site of bin ding to the S-1 pocket, was synthesized. Biological evaluation showed low n anomolar activity and modest selectivity toward different MMP subclasses, d elineating the importance of binding to the S-1 pocket for both activity an d selectivity.