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.
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).
authors.affiliation: Center for Organic and Medicinal Chemistry, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences ZHAW, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland. thomas.fischer@zhaw.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.affiliation: Center for Organic and Medicinal Chemistry, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences ZHAW, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland. rainer.riedl@zhaw.ch.
authors.forename: Rainer
authors.initials: R
authors.lastname: Riedl
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008024:Ligands; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D053509:Matrix Metalloproteinase 13; D015032:Zinc
keywords: lipophilic ligand efficiency; matrix metalloproteinase inhibitors; molecular recognition; organic synthesis; structure-based drug design; weak zinc binders