Design and Synthesis of Matrix Metalloproteinase Inhibitors Guided by Molecular Modeling. Picking the S1 Pocket Using Conformationally Constrained Inhibitors

Conformationally constrained MMP inhibitors based on a d-proline scaffold were designed using AutoDock as a modeling program. Thus a family of d-proline hydroxamic acids, having differentiated functionality at the site of binding to the S1 pocket, was synthesized. Biological evaluation showed low nanomolar activity and modest selectivity toward different MMP subclasses, delineating the importance of binding to the S1 pocket for both activity and selectivity.