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

Vernon Seow,David P Fairlie,Martin J Stoermer,Weijun Xu,W Mei Kok,Adam J Cotterell,Mei-Kwan Yau,Robert C Reid,Junxian Lim,Jacky Y Suen,Rink-Jan Lohman,Matthew J Sweet

doi:10.1038/srep24575

Vernon Seow, David P Fairlie + Show 10 more

Open Access

https://doi.org/10.1038/srep24575

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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.

Highlights

We debunk the almost universal perception that drugs need to be developed by increasing receptor affinity, potency, drug-likeness and oral bioavailability
A reduction of the maximal C5a responses was observed as the concentration of 3D53 increased, but there was no rightward shift of the curve typical of competitive or surmountable antagonism, consistent instead with insurmountable C5a receptor 1 (C5aR) antagonism by 3D53 (Fig. 2D)
The slopes for W54011 (Fig. 2H) and JJ47 (Fig. 2I) were both ~1, consistent with these compounds being competitive antagonists with C5a on human monocyte-derived macrophages (HMDM) and antagonist IC50 values being dependent on the concentration of C5a used

Summary

Introduction

We debunk the almost universal perception that drugs need to be developed by increasing receptor affinity, potency, drug-likeness (rule-of-five compliance) and oral bioavailability. We compare three antagonists with equal potency in vitro against activation of a GPCR and find that two compounds which are orally bioavailable and strictly obey the drug-likeness guidelines have inferior efficacy, even oral efficacy, to a third compound that comprehensively violates these rules and has dramatically reduced oral bioavailability. Drug-like small molecules do not share these disadvantages, but none have yet advanced through clinical trials. 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 in approaching drug discovery and development in order to successfully translate compounds to market

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