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Title: Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors

Abstract

Aberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold. Our crystal structures revealed buried hydrogen bond interactions are important. Molecular orbital analysis from quantum chemistry calculations dissects the chemical groups participating in these interactions. Free energy calculation supports the differential contributions of the amide group to the binding affinities of these inhibitors. Cell-based hemolysis assay confirmed these compounds inhibit factor D mediated complement activation via the alternative pathway. Our study highlights the important interactions contributing to the high potency of factor D inhibitors reported recently.

Authors:
 [1];  [2];  [1];  [1];  [3];  [1];  [1];  [1]
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  1. Univ. of Michigan, Ann Arbor, MI (United States)
  2. Taussig Cancer Inst., Cleveland, OH (United States)
  3. China Pharmaceutical Univ., Nanjing (China)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1438896
Resource Type:
Accepted Manuscript
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 7; Journal Issue: 12; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Amides; Peptides and proteins; Assays; Inhibitors; Noncovalent interactions; Paroxysmal nocturnal hemoglobinuria; age-related macular degeneration; complement system; complement factor D inhibitors; serine protease; enzyme inhibition assay; biolayer interferometry assay; crystal structure; quantum chemistry calculations; thermodynamic integration method; computational docking; molecular dynamics simulations; hemolysis assay

Citation Formats

Yang, Chao-Yie, Phillips, James G., Stuckey, Jeanne A., Bai, Longchuan, Sun, Haiying, Delproposto, James, Brown, William Clay, and Chinnaswamy, Krishnapriya. Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors. United States: N. p., 2016. Web. doi:10.1021/acsmedchemlett.6b00299.
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Yang, Chao-Yie, Phillips, James G., Stuckey, Jeanne A., Bai, Longchuan, Sun, Haiying, Delproposto, James, Brown, William Clay, & Chinnaswamy, Krishnapriya. Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors. United States. https://doi.org/10.1021/acsmedchemlett.6b00299
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Yang, Chao-Yie, Phillips, James G., Stuckey, Jeanne A., Bai, Longchuan, Sun, Haiying, Delproposto, James, Brown, William Clay, and Chinnaswamy, Krishnapriya. Thu . "Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors". United States. https://doi.org/10.1021/acsmedchemlett.6b00299. https://www.osti.gov/servlets/purl/1438896.
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@article{osti_1438896,
title = {Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors},
author = {Yang, Chao-Yie and Phillips, James G. and Stuckey, Jeanne A. and Bai, Longchuan and Sun, Haiying and Delproposto, James and Brown, William Clay and Chinnaswamy, Krishnapriya},
abstractNote = {Aberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold. Our crystal structures revealed buried hydrogen bond interactions are important. Molecular orbital analysis from quantum chemistry calculations dissects the chemical groups participating in these interactions. Free energy calculation supports the differential contributions of the amide group to the binding affinities of these inhibitors. Cell-based hemolysis assay confirmed these compounds inhibit factor D mediated complement activation via the alternative pathway. Our study highlights the important interactions contributing to the high potency of factor D inhibitors reported recently.},
doi = {10.1021/acsmedchemlett.6b00299},
journal = {ACS Medicinal Chemistry Letters},
number = 12,
volume = 7,
place = {United States},
year = {Thu Sep 15 00:00:00 EDT 2016},
month = {Thu Sep 15 00:00:00 EDT 2016}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acsmedchemlett.6b00299
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Citation Metrics:
Cited by: 13 works
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Figures / Tables:

Figure 1 Figure 1: (A) Examples of the structures of the covalent and noncovalent factor D inhibitors. (B) Structures of JH1-JH4, their IC50 and binding kinetic data with factor D. For the enzymatic assay, the IC50 values were determined by the average of at least two independent triplicate experiments. Binding kinetic datamore » were obtained from the averages of two independent experiments and the standard deviations are shown in the parentheses. (C) Enzymatic activities parameters24 of factor D obtained from Complement Technology and our recombinant protein as determined from the enzymatic assay.« less
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    Works referencing / citing this record:

    NMR 1 H-Shielding Constants of Hydrogen-Bond Donor Reflect Manifestation of the Pauli Principle
    journal, June 2018

    • Zarycz, M. Natalia C.; Fonseca Guerra, Célia
    • The Journal of Physical Chemistry Letters, Vol. 9, Issue 13
    • DOI: 10.1021/acs.jpclett.8b01502
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