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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

Comparative properties and in vitro potencies of C5aR antagonists.Top: Chemical structures for antagonists 3D53, W54011 and JJ47. Bottom: Properties and antagonist potencies of the three compounds. aMW = molecular weight, HBD = hydrogen bond donors, HBA = hydrogen bond acceptors, ClogP = calculated octanol-water partition coefficient, CLogS = calculated aqueous solubility, PSA = Polar surface area. bInhibition of Ca2+ release in different cells, under different conditions and against different concentrations of C5a. cVersus 100 nM rhC5a on neutrophils12. dVersus 0.1nM rhC5a on neutrophils14. eVersus 1.5 nM rhC5a on U937 cells15.
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f1: Comparative properties and in vitro potencies of C5aR antagonists.Top: Chemical structures for antagonists 3D53, W54011 and JJ47. Bottom: Properties and antagonist potencies of the three compounds. aMW = molecular weight, HBD = hydrogen bond donors, HBA = hydrogen bond acceptors, ClogP = calculated octanol-water partition coefficient, CLogS = calculated aqueous solubility, PSA = Polar surface area. bInhibition of Ca2+ release in different cells, under different conditions and against different concentrations of C5a. cVersus 100 nM rhC5a on neutrophils12. dVersus 0.1nM rhC5a on neutrophils14. eVersus 1.5 nM rhC5a on U937 cells15.

Mentions: Three C5aR antagonists 3D534111213, W5401114 and JJ4715 (Fig. 1) are compared here for antagonist potency, antagonist mechanism and duration of action in inhibiting C5aR-mediated human macrophage functions (calcium release, chemotaxis, inflammatory gene expression) and rat paw inflammation. 3D53 is a cyclic peptide designed in our laboratory4111213 on the back of initial peptide studies at Abbott16 and Merck17. It has been licensed as PMX53 and is safe and well tolerated in Phase I and II clinical trials. All three compounds are orally active, but W54011 and JJ47 are much more drug-like and rule-of-five compliant123 small organic compounds (Fig. 1). However, despite being less drug-like, comprehensively violating the rule-of-five, and being much less orally bioavailable, the cyclic peptide 3D53 is shown here to be far more efficacious, even when administered orally. This study demonstrates an important lesson in drug discovery and development, that ligand residence time on its receptor can trump rule-of-five considerations and be an overriding feature in dictating drug efficacy in vitro and in vivo, even oral efficacy for compounds with vastly inferior oral bioavailability. Our study highlights the need for more sophistication now in approaching drug discovery and development in order to successfully translate compounds to market.


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)

Comparative properties and in vitro potencies of C5aR antagonists.Top: Chemical structures for antagonists 3D53, W54011 and JJ47. Bottom: Properties and antagonist potencies of the three compounds. aMW = molecular weight, HBD = hydrogen bond donors, HBA = hydrogen bond acceptors, ClogP = calculated octanol-water partition coefficient, CLogS = calculated aqueous solubility, PSA = Polar surface area. bInhibition of Ca2+ release in different cells, under different conditions and against different concentrations of C5a. cVersus 100 nM rhC5a on neutrophils12. dVersus 0.1nM rhC5a on neutrophils14. eVersus 1.5 nM rhC5a on U937 cells15.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Comparative properties and in vitro potencies of C5aR antagonists.Top: Chemical structures for antagonists 3D53, W54011 and JJ47. Bottom: Properties and antagonist potencies of the three compounds. aMW = molecular weight, HBD = hydrogen bond donors, HBA = hydrogen bond acceptors, ClogP = calculated octanol-water partition coefficient, CLogS = calculated aqueous solubility, PSA = Polar surface area. bInhibition of Ca2+ release in different cells, under different conditions and against different concentrations of C5a. cVersus 100 nM rhC5a on neutrophils12. dVersus 0.1nM rhC5a on neutrophils14. eVersus 1.5 nM rhC5a on U937 cells15.
Mentions: Three C5aR antagonists 3D534111213, W5401114 and JJ4715 (Fig. 1) are compared here for antagonist potency, antagonist mechanism and duration of action in inhibiting C5aR-mediated human macrophage functions (calcium release, chemotaxis, inflammatory gene expression) and rat paw inflammation. 3D53 is a cyclic peptide designed in our laboratory4111213 on the back of initial peptide studies at Abbott16 and Merck17. It has been licensed as PMX53 and is safe and well tolerated in Phase I and II clinical trials. All three compounds are orally active, but W54011 and JJ47 are much more drug-like and rule-of-five compliant123 small organic compounds (Fig. 1). However, despite being less drug-like, comprehensively violating the rule-of-five, and being much less orally bioavailable, the cyclic peptide 3D53 is shown here to be far more efficacious, even when administered orally. This study demonstrates an important lesson in drug discovery and development, that ligand residence time on its receptor can trump rule-of-five considerations and be an overriding feature in dictating drug efficacy in vitro and in vivo, even oral efficacy for compounds with vastly inferior oral bioavailability. Our study highlights the need for more sophistication now in approaching drug discovery and development in order to successfully translate compounds to market.

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