Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

Seow, Vernon, Lim, Junxian, Cotterell, Adam J., Yau, Mei-Kwan, Xu, Weijun, Lohman, Rink-Jan, Kok, W. Mei, Stoermer, Martin J., Sweet, Matthew J., Reid, Robert C., Suen, Jacky Y. and Farilie, David P. (2016) Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists. Scientific Reports, 6 24575.1-24575.12. doi:10.1038/srep24575


Author Seow, Vernon
Lim, Junxian
Cotterell, Adam J.
Yau, Mei-Kwan
Xu, Weijun
Lohman, Rink-Jan
Kok, W. Mei
Stoermer, Martin J.
Sweet, Matthew J.
Reid, Robert C.
Suen, Jacky Y.
Farilie, David P.
Title Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2016-04-20
Year available 2016
Sub-type Article (original research)
DOI 10.1038/srep24575
Open Access Status DOI
Volume 6
Start page 24575.1
End page 24575.12
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing
Language eng
Subject 1000 General
Abstract 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 (3nM) 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 (t(1/2) similar to 20 h) than W54011 or JJ47 (t(1/2) similar to 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.
Formatted abstract
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 (3nM) 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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1028423
DP150104609
CE140100011
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 9 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 9 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 03 May 2016, 23:57:28 EST by Dr Rink-jan Lohman on behalf of Institute for Molecular Bioscience