Drugs for Allosteric Sites on Receptors

Wenthur, Cody J.; Gentry, Patrick R.; Mathews, Thomas P.; Lindsley, Craig W.

doi:10.1146/annurev-pharmtox-010611-134525

Cited by 224 publications

(281 citation statements)

References 88 publications

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“…In addition to GPCRs, there are now numerous allosteric ligands either marketed or in different stages of preclinical or clinical development for therapeutic targets such as ion channels, kinases, caspases, and phospholipases Wenthur et al, 2014). This highlights the fact that the paradigm is very broad and has gained substantial traction in modern drug discovery.…”

Section: Advances In Gpcr Allosterymentioning

confidence: 99%

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

2014

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It is now widely accepted that G protein-coupled receptors (GPCRs) are highly dynamic proteins that adopt multiple active states linked to distinct functional outcomes. Furthermore, these states can be differentially stabilized not only by orthosteric ligands but also by allosteric ligands acting at spatially distinct binding sites. The key pharmacologic characteristics of GPCR allostery include improved selectivity due to either greater sequence divergence between receptor subtypes and/or subtype-selective cooperativity, a ceiling level to the effect, probe dependence (whereby the magnitude and direction of the allosteric effect change with the nature of the interacting ligands), and the potential for biased signaling.Recent chemical biology developments are beginning to demonstrate how the incorporation of analytical pharmacology and operational modeling into the experimental workflow can enrich structure-activity studies of allostery and bias, and have also led to the discovery of a new class of hybrid orthosteric/ allosteric (bitopic) molecules. The potential for endogenous allosteric modulators to play a role in physiology and disease remains to be fully appreciated but will likely represent an important area for future studies. Finally, breakthroughs in structural and computational biology are beginning to unravel the mechanistic basis of GPCR allosteric modulation at the molecular level.

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Section: Advances In Gpcr Allosterymentioning

confidence: 99%

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

2014

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“…Because many allosteric proteins form homo-oligomeric complexes to modulate a ligand-induced biological response (2, 3), intersubunit communication must play a crucial role in the transduction of an allosteric signal (4, 5). Identifying the molecular mechanisms of intersubunit communication has important implications, from understanding how biological systems detect and transduce signals (6, 7) to reengineering of signaling proteins (8 -10) and to developing allosteric therapeutic modulators with enhanced affinities and specificities (11,12). Despite its importance, dissecting the mechanisms of transduction of allosteric signals from one protein subunit to another has proven difficult because it requires monitoring intermediate liganded states that are poorly populated, especially if the protein displays positive ligand binding cooperativity.…”

mentioning

confidence: 99%

Asymmetric configurations in a reengineered homodimer reveal multiple subunit communication pathways in protein allostery

Lanfranco

Gárate

Engdahl³

et al. 2017

Journal of Biological Chemistry

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Many allosteric proteins form homo-oligomeric complexes to regulate a biological function. In homo-oligomers, subunits establish communication pathways that are modulated by external stimuli like ligand binding. A challenge for dissecting the communication mechanisms in homo-oligomers is identifying intermediate liganded states, which are typically transiently populated. However, their identities provide the most mechanistic information on how ligand-induced signals propagate from bound to empty subunits. Here, we dissected the directionality and magnitude of subunit communication in a reengineered single-chain version of the homodimeric transcription factor cAMP receptor protein. By combining wild-type and mutant subunits in various asymmetric configurations, we revealed a linear relationship between the magnitude of cooperative effects and the number of mutant subunits. We found that a single mutation is sufficient to change the global allosteric behavior of the dimer even when one subunit was wild type. Dimers harboring two mutations with opposite cooperative effects had different allosteric properties depending on the arrangement of the mutations. When the two mutations were placed in the same subunit, the resulting cooperativity was neutral. In contrast, when placed in different subunits, the observed cooperativity was dominated by the mutation with strongest effects over cAMP affinity relative to wild type. These results highlight the distinct roles of intrasubunit interactions and intersubunit communication in allostery. Finally, dimers bound to either one or two cAMP molecules had similar DNA affinities, indicating that both asymmetric and symmetric liganded states activate DNA interactions. These studies have revealed the multiple communication pathways that homo-oligomers employ to transduce signals.Allosteric proteins are the basic building blocks in the transmission of biological signals, allowing communication between and within cells and from the extracellular environment to the cytosol (1). Because many allosteric proteins form homo-oligomeric complexes to modulate a ligand-induced biological response (2, 3), intersubunit communication must play a crucial role in the transduction of an allosteric signal (4, 5). Identifying the molecular mechanisms of intersubunit communication has important implications, from understanding how biological systems detect and transduce signals (6, 7) to reengineering of signaling proteins (8 -10) and to developing allosteric therapeutic modulators with enhanced affinities and specificities (11,12). Despite its importance, dissecting the mechanisms of transduction of allosteric signals from one protein subunit to another has proven difficult because it requires monitoring intermediate liganded states that are poorly populated, especially if the protein displays positive ligand binding cooperativity. Therefore, one of the remaining unresolved issues in allostery is dissecting the directionality of pathways of signal transmissions across protein subunits.A widely used s...

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“…This so-called orthosteric binding pocket/ site (Fig. 1a) can be bound with both native or synthetic ligands termed orthosteric ligands (6,7). Early drug development focused on the orthosteric site (8).…”

Section: Introductionmentioning

confidence: 99%

“…The application of allosteric drugs can enhance GABA A receptor activity in the treatment of CNS disorder and overcome shortcomings of traditional orthosteric compounds. The increasing number of both publications and new modulators reflects a general trend of developing allosteric modulators (7,17). Allosteric modulators are found to possess better receptor subtype selectivity when compared with orthosteric ligands (9,11,18,19).…”

Section: Introductionmentioning

confidence: 99%

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Feng

et al. 2015

AAPS J

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Abstract. Allosteric modulators of G protein-coupled receptors (GPCRs), which target at allosteric sites, have significant advantages against the corresponding orthosteric compounds including higher selectivity, improved chemical tractability or physicochemical properties, and reduced risk of receptor oversensitization. Bitopic ligands of GPCRs target both orthosteric and allosteric sites. Bitopic ligands can improve binding affinity, enhance subtype selectivity, stabilize receptors, and reduce side effects. Discovering allosteric modulators or bitopic ligands for GPCRs has become an emerging research area, in which the design of allosteric modulators is a key step in the detection of bitopic ligands. Radioligand binding and functional assays ([ 35 S]GTPγS and ERK1/2 phosphorylation) are used to test the effects for potential modulators or bitopic ligands. High-throughput screening (HTS) in combination with disulfide trapping and fragment-based screening are used to aid the discovery of the allosteric modulators or bitopic ligands of GPCRs. When used alone, these methods are costly and can often result in too many potential drug targets, including false positives. Alternatively, low-cost and efficient computational approaches are useful in drug discovery of novel allosteric modulators and bitopic ligands to help refine the number of targets and reduce the false-positive rates. This review summarizes the state-of-the-art computational methods for the discovery of modulators and bitopic ligands. The challenges and opportunities for future drug discovery are also discussed.

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Drugs for Allosteric Sites on Receptors

Cited by 224 publications

References 88 publications

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

Asymmetric configurations in a reengineered homodimer reveal multiple subunit communication pathways in protein allostery

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

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