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Discovery of Small Molecules for Fluorescent Detection of Complement Activation Product C3d

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    Discovery of Small Molecules for Fluorescent Detection of Complement Activation Product C3d
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    † Department of Bioengineering, University of California, Riverside, California 92521, United States
    ‡ Division of Mechanics, Research Center for Applied Sciences and Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
    § School of Pharmacy, National Taiwan University, Taipei 100, Taiwan
    ∥ Department of Medical Microbiology, University Medical Center, Utrecht, 3584 CX Utrecht, The Netherlands
    *Phone: +1-951-827-2696. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2015, 58, 24, 9535–9545
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    https://doi.org/10.1021/acs.jmedchem.5b01062
    Published November 27, 2015
    Copyright © 2015 American Chemical Society
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    Abstract

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    Complement activation plays a major role in many acute and chronic inflammatory conditions. C3d, a terminal product of complement activation, remains covalently attached to cells and is an excellent biomarker of complement-mediated inflammation. We employed a virtual high-throughput screening protocol to identify molecules with predicted binding to complement C3d and with intrinsic fluorescence properties to enable detection. Pharmacophore models were developed based on known C3d–ligand interactions and information from computational analysis of structural and molecular dynamics data. Iterative pharmacophore-based virtual screening was performed to identify druglike molecules with physicochemical similarity to the natural C3d ligand CR2. Hits from the pharmacophore screens were docked to C3d and ranked based on predicted binding free energies. Top-ranked molecules were selected for experimental validation of binding affinity to C3d, using microscale thermophoresis, and for their suitability to become molecular imaging agents, using fluorescence spectroscopy. This work serves as a foundation for identifying additional fluorescent molecules with high-affinity for C3d that will subsequently be explored as noninvasive in vivo diagnostics of complement-mediated inflammation, for spatiotemporal monitoring of disease progression, and for targeting therapeutics to sites of inflammation.

    Copyright © 2015 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01062.

    • Three tables listing pharmacophore features, selected compounds fluorescence quantum yields; four figures showing structures, docked poses, and binding sites (PDF)

    • Molecular formula strings (CSV)

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    This article is cited by 8 publications.

    1. Reed E. S. Harrison, Nehemiah T. Zewde, Yogesh B. Narkhede, Rohaine V. Hsu, Dimitrios Morikis, Valentine I. Vullev, Giulia Palermo. Factor H-Inspired Design of Peptide Biomarkers of the Complement C3d Protein. ACS Medicinal Chemistry Letters 2020, 11 (5) , 1054-1059. https://doi.org/10.1021/acsmedchemlett.9b00663
    2. Rohith R. Mohan, Mark Wilson, Ronald D. Gorham, Jr., Reed E. S. Harrison, Vasilios A. Morikis, Chris A. Kieslich, Asuka A. Orr, Alexis V. Coley, Phanourios Tamamis, Dimitrios Morikis. Virtual Screening of Chemical Compounds for Discovery of Complement C3 Ligands. ACS Omega 2018, 3 (6) , 6427-6438. https://doi.org/10.1021/acsomega.8b00606
    3. Rohith R. Mohan, Gary A. Huber, and Dimitrios Morikis . Electrostatic Steering Accelerates C3d:CR2 Association. The Journal of Physical Chemistry B 2016, 120 (33) , 8416-8423. https://doi.org/10.1021/acs.jpcb.6b02095
    4. Hyeong Won Kim, Mi-Kyeong Ko, So Hui Park, Seokwon Shin, Su-Mi Kim, Jong-Hyeon Park, Min Ja Lee. Bestatin, A Pluripotent Immunomodulatory Small Molecule, Drives Robust and Long-Lasting Immune Responses as an Adjuvant in Viral Vaccines. Vaccines 2023, 11 (11) , 1690. https://doi.org/10.3390/vaccines11111690
    5. Edwin R. Lampugnani, René H. Wink, Staffan Persson, Marc Somssich. The Toolbox to Study Protein–Protein Interactions in Plants. Critical Reviews in Plant Sciences 2018, 37 (4) , 308-334. https://doi.org/10.1080/07352689.2018.1500136
    6. Brandon L Garcia, D Andrew Skaff, Arindam Chatterjee, Anders Hanning, John K Walker, Gerald J Wyckoff, Brian V Geisbrecht. Identification of C3b-Binding Small-Molecule Complement Inhibitors Using Cheminformatics. The Journal of Immunology 2017, 198 (9) , 3705-3718. https://doi.org/10.4049/jimmunol.1601932
    7. M. Klika Škopić, O. Bugain, K. Jung, S. Onstein, S. Brandherm, T. Kalliokoski, A. Brunschweiger. Design and synthesis of DNA-encoded libraries based on a benzodiazepine and a pyrazolopyrimidine scaffold. MedChemComm 2016, 7 (10) , 1957-1965. https://doi.org/10.1039/C6MD00243A
    8. Yan Zhang, Jingjing Guo, Lanlan Li, Xuewei Liu, Xiaojun Yao, Huanxiang Liu. The solvent at antigen-binding site regulated C3d–CR2 interactions through the C-terminal tail of C3d at different ion strengths: insights from molecular dynamics simulation. Biochimica et Biophysica Acta (BBA) - General Subjects 2016, 1860 (10) , 2220-2231. https://doi.org/10.1016/j.bbagen.2016.05.002
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2015, 58, 24, 9535–9545
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.5b01062
    Published November 27, 2015
    Copyright © 2015 American Chemical Society
    Request reuse permissions

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