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

Fischer, Thomas; Riedl, Rainer

doi:10.3390/ijms17030314

Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-1683

Publication type:	Article in scientific journal
Type of review:	Peer review (publication)
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
DOI:	10.3390/ijms17030314 10.21256/zhaw-1683
Published in:	International Journal of Molecular Sciences
Volume(Issue):	17
Issue:	3/314
Issue Date:	2016
Publisher / Ed. Institution:	MDPI
ISSN:	1422-0067 1661-6596
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).
URI:	https://digitalcollection.zhaw.ch/handle/11475/2838
Fulltext version:	Published version
License (according to publishing contract):	CC BY 4.0: Attribution 4.0 International
Departement:	Life Sciences and Facility Management
Appears in collections:	Publikationen Life Sciences und Facility Management

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Fischer, T., & Riedl, R. (2016). 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. International Journal of Molecular Sciences, 17(3/314). https://doi.org/10.3390/ijms17030314

Fischer, T. and Riedl, R. (2016) ‘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’, International Journal of Molecular Sciences, 17(3/314). Available at: https://doi.org/10.3390/ijms17030314.

T. Fischer and R. Riedl, “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,” International Journal of Molecular Sciences, vol. 17, no. 3/314, 2016, doi: 10.3390/ijms17030314.

FISCHER, Thomas und Rainer RIEDL, 2016. 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. International Journal of Molecular Sciences. 2016. Bd. 17, Nr. 3/314. DOI 10.3390/ijms17030314

Fischer, Thomas, and Rainer Riedl. 2016. “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.” International Journal of Molecular Sciences 17 (3/314). https://doi.org/10.3390/ijms17030314.

Fischer, Thomas, and Rainer Riedl. “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.” International Journal of Molecular Sciences, vol. 17, no. 3/314, 2016, https://doi.org/10.3390/ijms17030314.