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Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin

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Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg, Germany
GE Healthcare Bio-Sciences AB, SE-751 84 Uppsala, Sweden
*Phone: +49 6421 28 21313. E-mail: [email protected]
Cite this: ACS Chem. Biol. 2017, 12, 1, 225–233
Publication Date (Web):November 29, 2016
https://doi.org/10.1021/acschembio.6b00979
Copyright © 2016 American Chemical Society

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    Abstract

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    Kinetic parameters of protein–ligand interactions are progressively acknowledged as valuable information for rational drug discovery. However, a targeted optimization of binding kinetics is not easy to achieve, and further systematic studies are necessary to increase the understanding about molecular mechanisms involved. We determined association and dissociation rate constants for 17 inhibitors of the metalloprotease thermolysin by surface plasmon resonance spectroscopy and correlated kinetic data with high-resolution crystal structures in complex with the protein. From the structure–kinetics relationship, we conclude that the strength of interaction with Asn112 correlates with the rate-limiting step of dissociation. This residue is located at the beginning of a β-strand motif that lines the binding cleft and is commonly believed to align a substrate for catalysis. A reduced mobility of the Asn112 side chain owing to an enhanced engagement in charge-assisted hydrogen bonds prevents the conformational adjustment associated with ligand release and transformation of the enzyme to its open state. This hypothesis is supported by kinetic data of ZFPLA, a known pseudopeptidic inhibitor of thermolysin, which blocks the conformational transition of Asn112. Interference with this retrograde induced-fit mechanism results in variation of the residence time of thermolysin inhibitors by a factor of 74 000. The high conservation of this structural motif within the M4 and M13 metalloprotease families underpins the importance of this feature and has significant implications for drug discovery.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.6b00979.

    • SPR measurements, experimental data from SPR measurements, experimental data from SPR measurements at varying ionic strength conditions, sensograms from SPR measurements, comparison of kinetic data from SPR and photometric inhibition assay, crystallographic tables, ligand synthesis and purification, and sequence alignment of representative M4 and M13 proteases (PDF)

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    Atomic coordinates and experimental details for the crystal structures of 5 and 6 (PDB codes 5LIF and 5LWD) will be released upon publication.

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    Cited By

    This article is cited by 13 publications.

    1. Jonathan Cramer, Stefan G. Krimmer, Andreas Heine, and Gerhard Klebe . Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors. Journal of Medicinal Chemistry 2017, 60 (13) , 5791-5799. https://doi.org/10.1021/acs.jmedchem.7b00490
    2. Chris Rechlin, Frithjof Scheer, Felix Terwesten, Tobias Wulsdorf, Ewa Pol, Veronica Fridh, Philipp Toth, Wibke E. Diederich, Andreas Heine, and Gerhard Klebe . Price for Opening the Transient Specificity Pocket in Human Aldose Reductase upon Ligand Binding: Structural, Thermodynamic, Kinetic, and Computational Analysis. ACS Chemical Biology 2017, 12 (5) , 1397-1415. https://doi.org/10.1021/acschembio.7b00062
    3. Jakov Ivkovic, Shalinee Jha, Christian Lembacher‐Fadum, Johannes Puschnig, Prashant Kumar, Viktoria Reithofer, Karl Gruber, Peter Macheroux, Rolf Breinbauer. Efficient Entropy‐Driven Inhibition of Dipeptidyl Peptidase III by Hydroxyethylene Transition‐State Peptidomimetics. Chemistry – A European Journal 2021, 27 (56) , 14108-14120. https://doi.org/10.1002/chem.202102204
    4. Doris A. Schuetz, Lars Richter, Riccardo Martini, Gerhard F. Ecker. A structure–kinetic relationship study using matched molecular pair analysis. RSC Medicinal Chemistry 2020, 11 (11) , 1285-1294. https://doi.org/10.1039/D0MD00178C
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    6. D. V. Borisov, A.V. Veselovsky. Ligand–Receptor Binding Kinetics in Drug Design. Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry 2020, 14 (3) , 228-240. https://doi.org/10.1134/S199075082003004X
    7. D.V. Borisov, A.V. Veselovsky. Ligand-receptor binding kinetics in drug design. Biomeditsinskaya Khimiya 2020, 66 (1) , 42-53. https://doi.org/10.18097/pbmc20206601042
    8. José P. Leite, Luís Gales. Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product. FEBS Letters 2019, 593 (1) , 128-137. https://doi.org/10.1002/1873-3468.13285
    9. Alexios N. Matralis, Dimitrios Xanthopoulos, Geneviève Huot, Stéphane Lopes-Paciencia, Charles Cole, Hugo de Vries, Gerardo Ferbeyre, Youla S. Tsantrizos. Molecular tools that block maturation of the nuclear lamin A and decelerate cancer cell migration. Bioorganic & Medicinal Chemistry 2018, 26 (20) , 5547-5554. https://doi.org/10.1016/j.bmc.2018.10.001
    10. Haixia Su, Yechun Xu. Application of ITC-Based Characterization of Thermodynamic and Kinetic Association of Ligands With Proteins in Drug Design. Frontiers in Pharmacology 2018, 9 https://doi.org/10.3389/fphar.2018.01133
    11. Xiaoshuang He, Yue Sui, Sicen Wang. Stepwise frontal affinity chromatography model for drug and protein interaction. Analytical and Bioanalytical Chemistry 2018, 410 (23) , 5807-5815. https://doi.org/10.1007/s00216-018-1194-4
    12. Hao Lu, James N Iuliano, Peter J Tonge. Structure–kinetic relationships that control the residence time of drug–target complexes: insights from molecular structure and dynamics. Current Opinion in Chemical Biology 2018, 44 , 101-109. https://doi.org/10.1016/j.cbpa.2018.06.002
    13. Sara T. Gebre, Scott A. Cameron, Lei Li, Y.S. Babu, Vern L. Schramm. Intracellular rebinding of transition-state analogues provides extended in vivo inhibition lifetimes on human purine nucleoside phosphorylase. Journal of Biological Chemistry 2017, 292 (38) , 15907-15915. https://doi.org/10.1074/jbc.M117.801779

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