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

Nordström, HelenaUppsala universitet,Institutionen för biokemi och organisk kemi (författare)

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.

Gossas, ThomasUppsala universitet,Institutionen för biokemi och organisk kemi(Swepub:uu)thgos121 (författare)
Hämäläinen, Markku (författare)
Källblad, Per (författare)
Nyström, Susanne (författare)
Wallberg, Hans (författare)
Danielson, U. Helena,1959-Uppsala universitet,Institutionen för biokemi och organisk kemi(Swepub:uu)helenads (författare)
Uppsala universitetInstitutionen för biokemi och organisk kemi (creator_code:org_t)

Ingår i:Journal of Medicinal Chemistry: American Chemical Society (ACS)51:12, s. 3449-34590022-26231520-4804

Av författaren/redakt...: Nordström, Helen ...; Gossas, Thomas; Hämäläinen, Mark ...; Källblad, Per; Nyström, Susanne; Wallberg, Hans; visa fler...; Danielson, U. He ...; visa färre...

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