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Title: Molecular recognition of the catalytic zinc(II) ion in MMP-13 : structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies
Authors : Fischer, Thomas
Riedl, Rainer
Published in : International Journal of Molecular Sciences
Volume(Issue) : 17
Issue : 3/314
Publisher / Ed. Institution : MDPI
Issue Date: 2016
License (according to publishing contract) : CC BY 4.0: Namensnennung 4.0 International
Type of review: Peer review (Publication)
Language : English
Subjects : Structure-based drug design; Medicinal chemistry; Organic chemistry
Subject (DDC) : 572: Biochemistry
615: Pharmacology and therapeutics
Abstract: Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91).
Departement: Life Sciences und Facility Management
Publication type: Article in scientific Journal
DOI : 10.3390/ijms17030314
ISSN: 1422-0067
Appears in Collections:Publikationen Life Sciences und Facility Management

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