Impact, determination and prediction of drug–receptor residence times for GPCRs

doi:10.1016/j.coph.2016.07.004

Current Opinion in Pharmacology

Volume 30, October 2016, Pages 22-26

https://doi.org/10.1016/j.coph.2016.07.004 Get rights and content

Highlights

•
Drug residence time is of fundamental importance as optimization parameter in GPCR drug design.
•
Experimental methods to determine the drug residence time on GPCRs are available.
•
Computationally predicting fragment on-rate and off-rate is possible, but very demanding.
•
Approximate methods to predict structure–kinetics relationships are already used in GPCR drug design.

The residence time of a ligand on a GPCR of interest has become an optimization parameter in many examples in drug design. Long residence times can counterbalance unfavorable pharmacokinetic parameters, contributing to compound safety, and short residence times can be a tool to avoid target related side effects. Unlike the prediction and interpretation of the structure–activity relationship (SAR) of a ligand class on a receptor, the understanding and prediction of the structure–kinetics relationship (SKR) is much more demanding. Experimental and computational approaches are described, which serve to either rationalize SKR or to predict the kinetic parameters such as on-rates and off-rates.

Graphical abstract

Introduction

Over decades, drug candidates were only assessed by their affinity towards a target derived from in vitro assays under equilibrium conditions. This setting is rarely predictive for the in vivo situation, where after absorption pharmacokinetic (PK) clearance drives the drugs excretion, causing a dynamic change in local ligand concentrations. Recently, target residence time (defined as τ = 1/k_off, with k_off being the off-rate of a ligand from a target) has become an important parameter in drug optimization programs, as it can counterbalance too fast drug elimination [1••, 2, 3, 4]. For several marketed drugs a very long residence time has been reported, which has been related to their long duration of action allowing once daily administration, leading to superior drugs with improved medication adherence [5]. Especially for the pharmaceutically highly relevant GPCRs many long lasting ligands have been reported, showing long lasting efficacy in vivo [6].

The advantage of a long residence time is only evident, if the pharmacokinetic clearance is faster than the ligand dissociation from the receptor. In this case one may observe target occupancy over an extended period although virtually no drug is left in the circulation. This concept is very plausible for GPCR antagonists, aiming for inhibition of a receptor, however the model has recently also been extended to GPCR agonists [7] where sustained endosomal signaling has been proposed. Examples for such long-lasting drugs, for example, come from the respiratory disease area, where the M3 receptor antagonist tiotropium and the β2-adrenoceptor agonist olodaterol demonstrate that a very long residence time translates into full-day efficacy upon once daily administration [8]. However, for some targets, such as the dopamine D2 receptor or the GluN2B receptor, a short residence time may be crucial in order to avoid mechanism-based side effects [6]. In a recent study by Dahl and Akerud [9^••] the interplay of PK and binding kinetics has been explored and authors propose to optimize ligand residence time until a sweet spot is reached, where target occupancy is still achievable within a reasonable time period and receptor binding outlasts the period of PK driven elimination significantly.

Section snippets

Measuring of off-rates and establishing structure–kinetics relationships

In a large number of studies the residence time of ligands on various GPCRs has been determined and several reviews collect and compare the data [6, 9••, 10••, 11]. Guo et al. [10^••] and Hoffmann et al. [12] have reported overviews of the most commonly employed methods to determine the residence time experimentally. In general, one can discriminate between methods that require a (radioactively or fluorescently) labeled ligand and label-free methods. While the second method sounds more general,

Computational approaches to assess binding kinetics

To this point only the difficulties in experimentally establishing SKR have been discussed, but now one can take the next step and attempt to predict SKR. Whereas for the prediction of affinities physically sound methods are applied in drug design on a regular basis [28^•], no practicable method exists for the prediction of residence times. In the following, several methods are reported which are used to quantitatively or qualitatively predict residence times. The universal tool for the

Conclusions

Over the last few years the importance of ligand residence time in drug development has been recognized and this parameter has now often been considered as an optimization goal during lead optimization, especially for GPCRs. Whereas the prediction and testing of affinity data of ligands is well established, the measurement, and even more the prediction of ligand on-and off-kinetics is much more demanding. For the experimental testing of off-rates from GPCRs several methods are available, but

Conflict of interest statement

CST is a full time employee at Boehringer Ingelheim Pharma GmbH & Co KG.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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View full text

Impact, determination and prediction of drug–receptor residence times for GPCRs

Highlights

Graphical abstract

Introduction

Section snippets

Measuring of off-rates and establishing structure–kinetics relationships

Computational approaches to assess binding kinetics

Conclusions

Conflict of interest statement

References and recommended reading

Mayo Clin Proc

Curr Top Med Chem

Pulm Pharmacol Ther

Drug Discov Today

Med Res Rev

J Med Chem

Biochemistry

Eur J Med Chem

Eur J Med Chem

J Med Chem

J Chem Inform Model

Proc Natl Acad Sci

The drug–target residence time model: a 10-year retrospective

Nat Rev Drug Discov

The role of target binding kinetics in drug discovery

ChemMedChem

Drug–target residence time and its implications for lead optimization

Nat Rev Drug Discov

Design strategies to address kinetics of drug binding and residence time

Bioorg Med Chem Lett

Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses?

Drug Discov Today

Target–drug interactions: first principles and their application to drug discovery

Drug Discov Today

Ligand residence time at G-protein-coupled receptors — why we should take our time to study it

Mol Pharmacol

Biophysical mapping of the adenosine A2A receptor

J Med Chem