Drug‐Target Residence Time—A Case for G Protein‐Coupled Receptors

Abstract

A vast number of marketed drugs act on G protein-coupled receptors (GPCRs), the most successful category of drug targets to date. These drugs usually possess high target affinity and selectivity, and such combined features have been the driving force in the early phases of drug discovery. However, attrition has also been high. Many investigational new drugs eventually fail in clinical trials due to a demonstrated lack of efficacy. A retrospective assessment of successfully launched drugs revealed that their beneficial effects in patients may be attributed to their long drug-target residence times (RTs). Likewise, for some other GPCR drugs short RT could be beneficial to reduce the potential for on-target side effects. Hence, the compounds' kinetics behavior might in fact be the guiding principle to obtain a desired and durable effect in vivo. We therefore propose that drug-target RT should be taken into account as an additional parameter in the lead selection and optimization process. This should ultimately lead to an increased number of candidate drugs moving to the preclinical development phase and on to the market. This review contains examples of the kinetics behavior of GPCR ligands with improved in vivo efficacy and summarizes methods for assessing drug-target RT.

Distinct Signaling Patterns of Allosteric Antagonism at the P2Y1 Receptor

“…from three independent experiments performed in duplicate. The K B values of MRS2500 and BPTU and slopes from Schild analysis from three separate experiments are listed in Table 1. residence time (Guo et al, 2014;Klein Herenbrink et al, 2016), signaling amplification (Hepler, 2014), probe dependence (Kenakin, 2008;Ehlert, 2013), and cell background (Kenakin, 2009), in addition to the possibility of the conformational selective antagonism of BPTU in different pathways (Edelstein and Changeux, 2016).…”

Ligand Residence Time at G-protein–Coupled Receptors—Why We Should Take Our Time To Study It

“…Within the last 10 years several excellent reviews have appeared on the general topic of drug-target residence time, each covering the topic from a different perspective (Copeland et al, 2006;Tummino and Copeland, 2008;Lu and Tonge, 2010;Dahl andAkerud, 2013, Vauquelin andCharlton, 2013;Guo et al, 2014 to name a few), and have highlighted this parameter for drug discovery. To keep this minireview focused, we will refer the reader to those articles or the recently published book Thermodynamics and Kinetics of Drug Binding (Keserü and Swinney, 2015) for an in-depth discussion, and we will focus on the concept of residence time at GPCRs.…”

The Added Value of Assessing Ligand–Receptor Binding Kinetics in Drug Discovery

“…Factors that influence target vulnerability (e.g., target desensitization, internalization, or recycling) should be taken into consideration as well in this step. Next, after an affinity-directed hit-to-lead campaign, medium-to highthroughput kinetic screening (see the review 2 and references therein for detailed information) can be initiated to prioritize scaffolds with desired BK for further lead optimization. This can be performed by extensive structure−kinetics relationship (SKR) studies in combination with classical equilibrium-based structure−activity relationship (SAR) studies.…”

“…Such inclusive application of kinetic metrics in the triage and advancement of best leads can be very informative, especially in the context of a series of compounds that are otherwise chemically and/or biologically similar. 1,2 The integrated use of kinetics-based evaluations also facilitates a more complete selectivity profiling of a lead compound on a number of targets. Approaches that utilize prolonged occupancy of the drug on the designated target while minimizing binding to off-target proteins may improve a drug candidate's therapeutic index and thus yield compounds with desired kinetic selectivity.…”