Identification of MMP-12 Inhibitors by Using Biosensor-Based Screening of a Fragment Library

01 January 2008

Nordström, H.; Gossas, T.; Hämäläinen, M.; Källblad, P.; Nyström, S.; Wallberg, H.; Danielson, U. H. (2008) J. Med. Chem.; 51(12); 3449-3459.

Small inhibitors of matrix metalloproteinase 12 (MMP-12) have been identified with a biosensor-based screening strategy and a specifically designed fragment library. The interaction between fragments and three variants of the target and a reference protein with an active-site zinc ion was measured continuously by surface plasmon resonance. The developed experimental design overcame the inherent instability of MMP-12 and allowed the identification of fragments that interacted specifically with the active-site of MMP-12 but not with the reference protein. The interaction with MMP-12 for selected compounds were analyzed for concentration dependence and saturability. Compounds interacting distinctly with the target were further evaluated by an activity-based assay, verifying MMP-12 inhibition. Two effective inhibitors were identified, and the compound with highest affinity was confirmed to be a competitive inhibitor with an IC50 of 290 nM and a ligand efficiency of 0.7 kcal/mol heavy atom. This procedure integrates selectivity and binding site identification into the screening procedure and does not require structure determination.

Link to PubMed

More publications


Stay Updated

Sign up for the Beactica newsletter to receive our latest news and updates