Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists.
Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3 nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1 -3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Vernon
V
Seow
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Junxian
J
Lim
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Adam J
AJ
Cotterell
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Mei-Kwan
MK
Yau
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Weijun
W
Xu
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Rink-Jan
RJ
Lohman
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
W Mei
WM
Kok
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Martin J
MJ
Stoermer
Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Matthew J
MJ
Sweet
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Robert C
RC
Reid
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Jacky Y
JY
Suen
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
David P
DP
Fairlie
D000818:Animals; D001682:Biological Availability; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051381:Rats; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
D007166:Immunosuppressive Agents; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a