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Identification of M...
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Nordström, HelenaUppsala universitet,Institutionen för biokemi och organisk kemi
(författare)
Identification of MMP-12 Inhibitors by Using Biosensor-Based Screening of a Fragment Library
- Artikel/kapitelEngelska2008
Förlag, utgivningsår, omfång ...
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2008-05-22
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American Chemical Society (ACS),2008
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-106025
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-106025URI
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https://doi.org/10.1021/jm8000289DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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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.
Ämnesord och genrebeteckningar
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Biochemistry
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Biokemi
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Biokemi
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Biochemistry
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Gossas, ThomasUppsala universitet,Institutionen för biokemi och organisk kemi(Swepub:uu)thgos121
(författare)
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Hämäläinen, Markku
(författare)
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Källblad, Per
(författare)
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Nyström, Susanne
(författare)
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Wallberg, Hans
(författare)
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Danielson, U. Helena,1959-Uppsala universitet,Institutionen för biokemi och organisk kemi(Swepub:uu)helenads
(författare)
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Uppsala universitetInstitutionen för biokemi och organisk kemi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Journal of Medicinal Chemistry: American Chemical Society (ACS)51:12, s. 3449-34590022-26231520-4804
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