Open AccessBuried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors
Author(s) -
Chao Yang,
James G. Phillips,
Jeanne A. Stuckey,
Longchuan Bai,
Haiying Sun,
James Delproposto,
William Clay Brown,
Krishnapriya Chinnaswamy
Publication year - 2016
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.6b00299
Subject(s) - hydrogen bond , potency , chemistry , amide , stereochemistry , complement system , alternative complement pathway , pyrrolidine , factor h , biochemistry , antibody , medicine , immunology , in vitro , molecule , organic chemistry
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.