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

Seow V, Lim J, Cotterell AJ, Yau MK, Xu W, Lohman RJ, Kok WM, Stoermer MJ, Sweet MJ, Reid RC, Suen JY, Fairlie DP - Sci Rep (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.

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 (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.

No MeSH data available.


Related in: MedlinePlus

Dependence of antagonist potencies (IC50) on C5a concentration in human monocyte-derived macrophages.Inhibitory responses of antagonist (A) 3D53, (B) W54011 and (C) JJ47 against various concentrations of C5a (300 nM, ●; 100 nM, ■; 30 nM, ▲; 10 nM, ◆; 3 nM, ▼; 1 nM, ★) relative to C5a (300 nM) inducing calcium release in HMDM (100%). Calculated pIC50 ± SEM and IC50 values for the three C5aR antagonists are summarized in the table versus concentration of C5a. Error bars are means ± SEM of three independent experiments (n = 3).
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f3: Dependence of antagonist potencies (IC50) on C5a concentration in human monocyte-derived macrophages.Inhibitory responses of antagonist (A) 3D53, (B) W54011 and (C) JJ47 against various concentrations of C5a (300 nM, ●; 100 nM, ■; 30 nM, ▲; 10 nM, ◆; 3 nM, ▼; 1 nM, ★) relative to C5a (300 nM) inducing calcium release in HMDM (100%). Calculated pIC50 ± SEM and IC50 values for the three C5aR antagonists are summarized in the table versus concentration of C5a. Error bars are means ± SEM of three independent experiments (n = 3).

Mentions: The antagonist IC50 value for 3D53 was independent of C5a concentration, maintaining potency against low (1 nM) and high (300 nM) concentrations of C5a (Fig. 3A). On the other hand, W54011 lost most of its antagonist activity against 100 nM C5a (Fig. 3B), with JJ47 being even less potent and losing its antagonist activity against just 10 nM C5a (Fig. 3C). Clearly, W54011 and JJ47 are only antagonists if measured against very low concentrations of C5a, and are unlikely to be very effective in vivo under pathophysiological conditions. Accordingly, for inflammatory diseases such as sepsis19 or for chronic disease where concentrations of C5a can be as high as 10–100 nM, neither W54011 nor JJ47 would be expected to be very effective antagonists.


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

Seow V, Lim J, Cotterell AJ, Yau MK, Xu W, Lohman RJ, Kok WM, Stoermer MJ, Sweet MJ, Reid RC, Suen JY, Fairlie DP - Sci Rep (2016)

Dependence of antagonist potencies (IC50) on C5a concentration in human monocyte-derived macrophages.Inhibitory responses of antagonist (A) 3D53, (B) W54011 and (C) JJ47 against various concentrations of C5a (300 nM, ●; 100 nM, ■; 30 nM, ▲; 10 nM, ◆; 3 nM, ▼; 1 nM, ★) relative to C5a (300 nM) inducing calcium release in HMDM (100%). Calculated pIC50 ± SEM and IC50 values for the three C5aR antagonists are summarized in the table versus concentration of C5a. Error bars are means ± SEM of three independent experiments (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837355&req=5

f3: Dependence of antagonist potencies (IC50) on C5a concentration in human monocyte-derived macrophages.Inhibitory responses of antagonist (A) 3D53, (B) W54011 and (C) JJ47 against various concentrations of C5a (300 nM, ●; 100 nM, ■; 30 nM, ▲; 10 nM, ◆; 3 nM, ▼; 1 nM, ★) relative to C5a (300 nM) inducing calcium release in HMDM (100%). Calculated pIC50 ± SEM and IC50 values for the three C5aR antagonists are summarized in the table versus concentration of C5a. Error bars are means ± SEM of three independent experiments (n = 3).
Mentions: The antagonist IC50 value for 3D53 was independent of C5a concentration, maintaining potency against low (1 nM) and high (300 nM) concentrations of C5a (Fig. 3A). On the other hand, W54011 lost most of its antagonist activity against 100 nM C5a (Fig. 3B), with JJ47 being even less potent and losing its antagonist activity against just 10 nM C5a (Fig. 3C). Clearly, W54011 and JJ47 are only antagonists if measured against very low concentrations of C5a, and are unlikely to be very effective in vivo under pathophysiological conditions. Accordingly, for inflammatory diseases such as sepsis19 or for chronic disease where concentrations of C5a can be as high as 10–100 nM, neither W54011 nor JJ47 would be expected to be very effective antagonists.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.

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 (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.

No MeSH data available.


Related in: MedlinePlus