The Role of Target Binding Kinetics in Drug Discovery

Guo, Dong; Heitman, Laura H.; IJzerman, Adriaan P.

doi:10.1002/cmdc.201500310

Cited by 44 publications

(53 citation statements)

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“…Pharmacologists are accustomed to using the equilibrium dissociation constant (K d ) as a guiding principle for drug design. Recently, there is increasing appreciation in the GPCR pharmacology field for the relevance of receptor residence time (¼ 1/k off ) of ligand (50), and hence a growing need to develop new assays for quantifying ligand binding and dissociation kinetics. In this study, we harnessed the unique photochemistry of Rho to develop energy transfer-based kinetic assays.…”

Section: Comparison Of Ligand Binding In Rho and Other Gpcrsmentioning

confidence: 99%

The Energetics of Chromophore Binding in the Visual Photoreceptor Rhodopsin

Tian

Sakmar

Huber

2017

Biophysical Journal

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The visual photoreceptor rhodopsin is a prototypical G-protein-coupled receptor (GPCR) that stabilizes its inverse agonist ligand, 11-cis-retinal (11CR), by a covalent, protonated Schiff base linkage. In the visual dark adaptation, the fundamental molecular event after photobleaching of rhodopsin is the recombination reaction between its apoprotein opsin and 11CR. Here we present a detailed analysis of the kinetics and thermodynamics of this reaction, also known as the "regeneration reaction". We compared the regeneration of purified rhodopsin reconstituted into phospholipid/detergent bicelles with rhodopsin reconstituted into detergent micelles. We found that the lipid bilayer of bicelles stabilized the chromophore-free opsin over the long timescale required for the regeneration experiments, and also facilitated the ligand reuptake binding reaction. We utilized genetic code expansion and site-specific bioorthogonal labeling of rhodopsin with Alexa488 to enable, to our knowledge, a novel fluorescence resonance energy transfer-based measurement of the binding kinetics between opsin and 11CR. Based on these results, we report a complete energy diagram for the regeneration reaction of rhodopsin. We show that the dissociation reaction of rhodopsin to 11CR and opsin has a 25-pM equilibrium dissociation constant, which corresponds to only 0.3 kcal/mol stabilization compared to the noncovalent, tightly bound antagonist-GPCR complex of iodopindolol and β-adrenergic receptor. However, 11CR dissociates four orders-of-magnitude slower than iodopindolol, which corresponds to a 6-kcal/mol higher dissociation free energy barrier. We further used isothermal titration calorimetry to show that ligand binding in rhodopsin is enthalpy driven with -22 kcal/mol, which is 12 kcal/mol more stable than the antagonist-GPCR complex. Our data provide insights into the ligand-receptor binding reaction for rhodopsin in particular, and for GPCRs more broadly.

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Section: Comparison Of Ligand Binding In Rho and Other Gpcrsmentioning

confidence: 99%

The Energetics of Chromophore Binding in the Visual Photoreceptor Rhodopsin

Tian

Sakmar

Huber

2017

Biophysical Journal

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“…229,230 Another issue to take into consideration is target vulnerability, e.g., receptor desensitization, internalization, degradation and recycling. 88 The A2A 231 , A2B 232 and A3 233 ARs have all been observed with rapid desensitization upon agonist treatment, with A3AR desensitization the faster process. 234 Posttranslational target modifications such as phosphorylation and ubiquitination also affect the target's half-life of A2A 235 , A2B 236 and A3 237 ARs leading to the recruitment of arrestins and subsequent sequestration from the plasma membrane.…”

Section: Characterization Of Ligand-receptor Binding Kinetics In Livimentioning

confidence: 99%

Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors

2016

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Ligand-receptor binding kinetics is an emerging topic in the drug research community. Over the past years, medicinal chemistry approaches from a kinetic perspective have been increasingly applied to G protein-coupled receptors including the adenosine receptors (AR), which are involved in a plethora of physiological and pathological conditions. The study of ligand-AR binding kinetics offers room for detailed structure-kinetics relationships next to more traditional structure-activity relationships. Their combination may facilitate the triage of candidate compounds in hit-to-lead campaigns. Furthermore, kinetic studies also help in understanding AR allosterism. Allosteric modulation may yield a change in the activity and conformation of a receptor resulting from the binding of a compound at a site distinct from where the endogenous agonist adenosine binds. Hence, in this Review, we summarize available data and evidence for the binding kinetics of orthosteric and allosteric AR ligands. We hope this Review will raise awareness to consider the kinetic aspects of drug-target interactions on both ARs and other drug targets.

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“…4 Recently, a drug discovery pipeline that integrates ligand−receptor BK has been proposed as a prospective strategy for drug discovery and development. 1 As shown in Figure 1, it might be beneficial to take BK into account immediately from the target validation stage and onward. One should consider whether a long or short RT is desired for improved efficacy, optimal duration of action, decreased mechanism-based toxicity, or desired on-set of drug action, respectively.…”

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confidence: 99%

“…Understanding ligand−receptor BK can be beneficial at all stages of the drug discovery process, but its highest impact is probably in the lead identification and optimization phase. 1 At this stage, a series of candidate compounds can be systematically examined for their SKR, which is complementary to the classical SAR. 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.…”

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confidence: 99%

“…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.…”

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confidence: 99%

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

Guo

Heitman

IJzerman

2016

ACS Med. Chem. Lett.

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In the past decade drug research community has started to appreciate the indispensable role of ligand−receptor binding kinetics (BK) in drug discovery. Next to the classical equilibrium-based drug evaluation process with affinity and potency values as outcomes, kinetic investigation of the ligand−receptor interaction can aid compound triage in the hit-to-lead campaign and provide additional information to understand the molecular mechanism of drug action. Translational models incorporating BK are emerging as well, which represent powerful tools for the prediction of in vivo effects. In this viewpoint we will summarize some recent findings and discuss and emphasize the added value of ligand−receptor binding kinetics in drug research.

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The Role of Target Binding Kinetics in Drug Discovery

Cited by 44 publications

References 44 publications

The Energetics of Chromophore Binding in the Visual Photoreceptor Rhodopsin

The Energetics of Chromophore Binding in the Visual Photoreceptor Rhodopsin

Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors

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

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