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Journal articles on the topic 'Allosteric modulators'

Author: Grafiati

Published: 4 June 2021

Last updated: 26 July 2025

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1

Manetti, Dina, Silvia Dei, Hugo R. Arias, et al. "Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators." Molecules 28, no. 3 (2023): 1270. http://dx.doi.org/10.3390/molecules28031270.

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Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on the compounds that have been shown or have been designed to interact with nicotinic receptors as allosteric modulators of different subtypes, mainly α7 and α4β2. Minimal chemical changes can cause a different pharmacological profile, which can then lead to the desig

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2

Akimoto, Madoka, Karla Martinez Pomier, Bryan VanSchouwen, Jung Ah Byun, Mariia Khamina, and Giuseppe Melacini. "Allosteric pluripotency: challenges and opportunities." Biochemical Journal 479, no. 7 (2022): 825–38. http://dx.doi.org/10.1042/bcj20210528.

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Allosteric pluripotency arises when the functional response of an allosteric receptor to an allosteric stimulus depends on additional allosteric modulators. Here, we discuss allosteric pluripotency as observed in the prototypical Protein Kinase A (PKA) as well as in other signaling systems, from typical multidomain signaling proteins to bacterial enzymes. We identify key drivers of pluripotent allostery and illustrate how hypothesizing allosteric pluripotency may solve apparent discrepancies currently present in the literature regarding the dual nature of known allosteric modulators. We also o

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3

Langmead, Christopher J. "Screening for Positive Allosteric Modulators: Assessment of Modulator Concentration-Response Curves as a Screening Paradigm." Journal of Biomolecular Screening 12, no. 5 (2007): 668–76. http://dx.doi.org/10.1177/1087057107301854.

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Targeting allosteric binding sites represents a powerful mechanism for selectively modulating receptor function. The advent of functional assays as the screening method of choice is leading to an increase in the number of allosteric modulators identified. These include positive allosteric modulators that can increase the affinity of the orthosteric agonist and potentiate the evoked response. A common method for screening for positive allosteric modulators is to examine a concentration-response (C/R) curve to the putative modulator in the presence of a single, low concentration of agonist. The

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Homsher, Michelle F., Douglas C. Beshore, Jason Cassaday, et al. "High-Throughput Agonist Shift Assay Development for the Analysis of M1-Positive Allosteric Modulators." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 8 (2017): 1060–66. http://dx.doi.org/10.1177/2472555217705373.

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Agonist shift assays feature cross-titrations of allosteric modulators and orthosteric ligands. Information generated in agonist shift assays can include a modulator’s effect on the orthosteric agonist’s potency (alpha) and efficacy (beta), as well as direct agonist activity of the allosteric ligand (tauB) and the intrinsic binding affinity of the modulator to the unoccupied receptor (KB). Because of the heavy resource demand and complex data handling, these allosteric parameters are determined infrequently during the course of a drug discovery program and on a relatively small subset of compo

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Goričan, Tjaša, and Simona Golič Grdadolnik. "Insights into the Allosteric Regulation of Human Hsp90 Revealed by NMR Spectroscopy." Biomolecules 15, no. 1 (2024): 37. https://doi.org/10.3390/biom15010037.

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Human heat shock protein 90 (Hsp90) is one of the most important chaperones that play a role in the late stages of protein folding. Errors in the process of the chaperone cycle can lead to diseases such as cancer and neurodegenerative diseases. Therefore, the activity of Hsp90 must be carefully regulated. One of the possibilities is allosteric regulation by its natural allosteric modulators—nucleotides, co-chaperones and client proteins—and synthetic small-molecule allosteric modulators, such as those targeting the middle domain or the C-terminal domain (CTD) of Hsp90. Since no experimentally

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Wang, Huiqun, Danni Cao, James C. Gillespie, et al. "Exploring the putative mechanism of allosteric modulations by mixed-action kappa/mu opioid receptor bitopic modulators." Future Medicinal Chemistry 13, no. 6 (2021): 551–73. http://dx.doi.org/10.4155/fmc-2020-0308.

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The modulation and selectivity mechanisms of seven mixed-action kappa opioid receptor (KOR)/mu opioid receptor (MOR) bitopic modulators were explored. Molecular modeling results indicated that the ‘message’ moiety of seven bitopic modulators shared the same binding mode with the orthosteric site of the KOR and MOR, whereas the ‘address’ moiety bound with different subdomains of the allosteric site of the KOR and MOR. The ‘address’ moiety of seven bitopic modulators bound to different subdomains of the allosteric site of the KOR and MOR may exhibit distinguishable allosteric modulations to the

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Trinh, Phuc N. H., Lauren T. May, Katie Leach, and Karen J. Gregory. "Biased agonism and allosteric modulation of metabotropic glutamate receptor 5." Clinical Science 132, no. 21 (2018): 2323–38. http://dx.doi.org/10.1042/cs20180374.

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Metabotropic glutamate receptors belong to class C G-protein-coupled receptors and consist of eight subtypes that are ubiquitously expressed throughout the central nervous system. In recent years, the metabotropic glutamate receptor subtype 5 (mGlu5) has emerged as a promising target for a broad range of psychiatric and neurological disorders. Drug discovery programs targetting mGlu5 are primarily focused on development of allosteric modulators that interact with sites distinct from the endogenous agonist glutamate. Significant efforts have seen mGlu5 allosteric modulators progress into clinic

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8

Żuk, Justyna, Damian Bartuzi, Andrea G. Silva, et al. "Allosteric modulation of dopamine D2L receptor in complex with Gi1 and Gi2 proteins: the effect of subtle structural and stereochemical ligand modifications." Pharmacological Reports 74, no. 2 (2022): 406–24. http://dx.doi.org/10.1007/s43440-021-00352-x.

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Abstract Background Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays one of the hot topics in drug discovery. In particular, allosteric modulators of D2 receptor have been proposed as potential modern therapeutics to treat schizophrenia and Parkinson’s disease. Methods To address some subtle structural and stereochemical aspects of allosteric modulation of D2 receptor, we performed extensive in silico studies of both enantiomers of two compounds (compound 1 and compound 2), and one of them (compound 2) was synthesized as a racemate in-house and studied in vitro. Results

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9

Christian, Catherine A., and John R. Huguenard. "Sniffer patch laser uncaging response (SPLURgE): an assay of regional differences in allosteric receptor modulation and neurotransmitter clearance." Journal of Neurophysiology 110, no. 7 (2013): 1722–31. http://dx.doi.org/10.1152/jn.00319.2013.

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Allosteric modulators exert actions on neurotransmitter receptors by positively or negatively altering the effective response of these receptors to their respective neurotransmitter. γ-Aminobutyric acid (GABA) type A ionotropic receptors (GABAARs) are major targets for allosteric modulators such as benzodiazepines, neurosteroids, and barbiturates. Analysis of substances that produce similar effects has been hampered by the lack of techniques to assess the localization and function of such agents in brain slices. Here we describe measurement of the sniffer patch laser uncaging response (SPLURgE

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Leach, Katie, Adriel Wen, Anna E. Cook, Patrick M. Sexton, Arthur D. Conigrave, and Arthur Christopoulos. "Impact of Clinically Relevant Mutations on the Pharmacoregulation and Signaling Bias of the Calcium-Sensing Receptor by Positive and Negative Allosteric Modulators." Endocrinology 154, no. 3 (2013): 1105–16. http://dx.doi.org/10.1210/en.2012-1887.

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Abstract Cinacalcet is predominantly used to treat secondary hyperparathyroidism due to end-stage renal failure, but, more recently, its potential clinical efficacy in treating patients with loss-of-function mutations in the calcium-sensing receptor (CaSR) has been recognized. Many clinically relevant CaSR mutations are located in the heptahelical membrane spanning and extracellular loop regions of the receptor, where allosteric modulators are predicted to bind. The aim of the present study was to investigate the impact of such mutations on the pharmacoregulation of the CaSR by the positive an

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11

Zhou, Qingtong, Wanjing Guo, Antao Dai, et al. "Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening." Biomolecules 11, no. 7 (2021): 929. http://dx.doi.org/10.3390/biom11070929.

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Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interaction

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12

Miao, Yinglong, Dahlia Anne Goldfeld, Ee Von Moo, et al. "Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor." Proceedings of the National Academy of Sciences 113, no. 38 (2016): E5675—E5684. http://dx.doi.org/10.1073/pnas.1612353113.

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Design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors, and may, for certain families of receptors, only be achieved via identification of chemically diverse allosteric modulators. Here, the extracellular vestibule of the M2 muscarinic acetylcholine receptor (mAChR) is targeted for structure-based design of allosteric modulators. Accelerated molecular dynamics (aMD) simulations were performed to construct structural ensembles that account for the receptor flexibility. Compounds obtained from the National Cancer Instit

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13

KENAKIN, TERRY. "Allosteric Agonist Modulators." Journal of Receptors and Signal Transduction 27, no. 4 (2007): 247–59. http://dx.doi.org/10.1080/10799890701509000.

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14

Nerín-Fonz, Francho, and Zoe Cournia. "Machine learning approaches in predicting allosteric sites." Current Opinion in Structural Biology 85 (February 13, 2024): 102774. https://doi.org/10.5281/zenodo.10658858.

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Allosteric regulation is a fundamental biological mechanism that can control critical cellular processes via allosteric modulator binding to protein distal functional sites. The advantages of allosteric modulators over orthosteric ones have sparked the development of numerous computational approaches, such as the identification of allosteric binding sites, to facilitate allosteric drug discovery. Building on the success of machine learning (ML) models for solving complex problems in biology and chemistry, several ML models for predicting allosteric sites have been developed. In this review, we

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15

Christopoulos, A., L. T. May, V. A. Avlani, and P. M. Sexton. "G-protein-coupled receptor allosterism: the promise and the problem(s)." Biochemical Society Transactions 32, no. 5 (2004): 873–77. http://dx.doi.org/10.1042/bst0320873.

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Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more ‘physiological’ regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validatio

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16

Odoemelam, Chiemela S., Elena Hunter, John Simms, et al. "In Silico Ligand Docking Approaches to Characterise the Binding of Known Allosteric Modulators to the Glucagon-Like Peptide 1 Receptor and Prediction of ADME/Tox Properties." Applied Biosciences 1, no. 2 (2022): 143–62. http://dx.doi.org/10.3390/applbiosci1020010.

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The glucagon-like peptide 1 receptor (GLP-1R) is a member of the family (or class) B G-protein-coupled receptor (GPCR). The receptor is a regulator of insulin and a key target in treating Type 2 diabetes mellitus. In this investigation, computational chemistry techniques such as molecular docking were combined with in silico ADME/Tox predictions to determine the position and structure of the allosteric binding site, as well as to examine how the allosteric modulators bind to the binding site. In silico evaluation was used to evaluate the ADME/Tox properties of the allosteric modulators. The fi

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17

Fasciani, Irene, Francesco Petragnano, Gabriella Aloisi, et al. "Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics." Pharmaceuticals 13, no. 11 (2020): 388. http://dx.doi.org/10.3390/ph13110388.

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Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthoster

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Johnson, M. P., E. S. Nisenbaum, T. H. Large, R. Emkey, M. Baez, and A. E. Kingston. "Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists." Biochemical Society Transactions 32, no. 5 (2004): 881–87. http://dx.doi.org/10.1042/bst0320881.

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Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonis

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Chen, Y., and P. J. Conn. "mGluR5 positive allosteric modulators." Drugs of the Future 33, no. 4 (2008): 355. http://dx.doi.org/10.1358/dof.2008.033.04.1186966.

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Kaczor, Agnieszka A., Tomasz M. Wróbel, and Damian Bartuzi. "Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis." Molecules 28, no. 1 (2022): 178. http://dx.doi.org/10.3390/molecules28010178.

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Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. Allosteric modulators, i.e., compounds which bind in a receptor site topologically distinct from orthosteric sites, exhibit a number of advantages. They are more selective, safer and display a ceiling effect which prevents overdosing. Allosteric modulators of dopamine D2 receptor are potential drugs against a number of psychiatric and neurological diseases, such as schizophrenia and Parkinson’s disease. In this review, an insightful summary of current research on D2 receptor modulators

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Milanos, Sinem, Katharina Kuenzel, Daniel F. Gilbert, et al. "Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation." Biological Chemistry 399, no. 6 (2018): 549–63. http://dx.doi.org/10.1515/hsz-2017-0262.

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Abstract GABAA receptors are ligand-gated anion channels that form pentameric arrangements of various subunits. Positive allosteric modulators of GABAA receptors have been reported as being isolated either from plants or synthesized analogs of known GABAA receptor targeting drugs. Recently, we identified monoterpenes, e.g. myrtenol as a positive allosteric modulator at α1β2 GABAA receptors. Here, along with pharmacophore-based virtual screening studies, we demonstrate that scaffold modifications of myrtenol resulted in the loss of modulatory activity. Two independent approaches, fluorescence-b

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Kondej, Magda, Piotr Stępnicki, and Agnieszka A. Kaczor. "Multi-Target Approach for Drug Discovery against Schizophrenia." International Journal of Molecular Sciences 19, no. 10 (2018): 3105. http://dx.doi.org/10.3390/ijms19103105.

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Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypo

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Jakubik, Jan, and Esam E. El-Fakahany. "Current Advances in Allosteric Modulation of Muscarinic Receptors." Biomolecules 10, no. 2 (2020): 325. http://dx.doi.org/10.3390/biom10020325.

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Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here,

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Sheik Amamuddy, Olivier, Wayde Veldman, Colleen Manyumwa, et al. "Integrated Computational Approaches and Tools for Allosteric Drug Discovery." International Journal of Molecular Sciences 21, no. 3 (2020): 847. http://dx.doi.org/10.3390/ijms21030847.

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Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although n

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Burford, N. T., M. J. Clark, T. S. Wehrman, et al. "Discovery of positive allosteric modulators and silent allosteric modulators of the -opioid receptor." Proceedings of the National Academy of Sciences 110, no. 26 (2013): 10830–35. http://dx.doi.org/10.1073/pnas.1300393110.

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Fyfe, Tim J., Peter J. Scammells, J. Robert Lane, and Ben Capuano. "Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D1 Receptor." Molecules 26, no. 13 (2021): 3799. http://dx.doi.org/10.3390/molecules26133799.

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(1) Background: Two first-in-class racemic dopamine D1 receptor (D1R) positive allosteric modulator (PAM) chemotypes (1 and 2) were identified from a high-throughput screen. In particular, due to its selectivity for the D1R and reported lack of intrinsic activity, compound 2 shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of 2 using chiral auxiliaries derived from (R)- and (S)-3-hydr

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Gado, Francesca, Serena Meini, Simone Bertini, Maria Digiacomo, Marco Macchia, and Clementina Manera. "Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery." Future Medicinal Chemistry 11, no. 15 (2019): 2019–37. http://dx.doi.org/10.4155/fmc-2019-0005.

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Allosteric modulators of cannabinoid receptors hold great therapeutic potential, as they do not possess intrinsic efficacy, but instead enhance or diminish the receptor's response of orthosteric ligands allowing for the tempering of cannabinoid receptor signaling without the desensitization, tolerance and dependence. Allosteric modulators of cannabinoid receptors have numerous advantages over the orthosteric ligands such as higher receptor type selectivity, probe dependence and biased signaling, so they have a great potential to separate the therapeutic benefits from side effects own of orthos

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Cohen, Shira, Faina Barer, Sara Bar-Yehuda, Adriaan P. IJzerman, Kenneth A. Jacobson, and Pnina Fishman. "A3Adenosine Receptor Allosteric Modulator Induces an Anti-Inflammatory Effect:In VivoStudies and Molecular Mechanism of Action." Mediators of Inflammation 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/708746.

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The A3adenosine receptor (A3AR) is overexpressed in inflammatory cells and in the peripheral blood mononuclear cells of individuals with inflammatory conditions. Agonists to the A3AR are known to induce specific anti-inflammatory effects upon chronic treatment. LUF6000 is an allosteric compound known to modulate the A3AR and render the endogenous ligand adenosine to bind to the receptor with higher affinity. The advantage of allosteric modulators is their capability to target specifically areas where adenosine levels are increased such as inflammatory and tumor sites, whereas normal body cells

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Amusengeri, Arnold, Lindy Astl, Kevin Lobb, Gennady M. Verkhivker, and Özlem Tastan Bishop. "Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Plasmodium falciparum Hsp70s." International Journal of Molecular Sciences 20, no. 22 (2019): 5574. http://dx.doi.org/10.3390/ijms20225574.

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Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control me

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Changeux, Jean-Pierre. "The nicotinic acetylcholine receptor: a typical ‘allosteric machine’." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (2018): 20170174. http://dx.doi.org/10.1098/rstb.2017.0174.

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The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with the classical mechanism of competitive, steric, interaction between ligands for a common site, allosteric interactions take place between topographically distinct sites and are mediated by a discrete and reversible conformational change of the protein. The concept was soon extended to membrane receptors for neurotransmitters and shown to apply to the signal transduction process which, in the case of the acetylcholine nicotinic

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Hou, Tianling, Yuemin Bian, Terence McGuire, and Xiang-Qun Xie. "Integrated Multi-Class Classification and Prediction of GPCR Allosteric Modulators by Machine Learning Intelligence." Biomolecules 11, no. 6 (2021): 870. http://dx.doi.org/10.3390/biom11060870.

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G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cell surface receptors that respond to various extracellular signals. The allosteric modulation of GPCRs has emerged in recent years as a promising approach for developing target-selective therapies. Moreover, the discovery of new GPCR allosteric modulators can greatly benefit the further understanding of GPCR cell signaling mechanisms. It is critical but also challenging to make an accurate distinction of modulators for different GPCR groups in an efficient and effective manner. In this study, we focus on an 11-clas

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Korkutata, Mustafa, Lokesh Agrawal, and Michael Lazarus. "Allosteric Modulation of Adenosine A2A Receptors as a New Therapeutic Avenue." International Journal of Molecular Sciences 23, no. 4 (2022): 2101. http://dx.doi.org/10.3390/ijms23042101.

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The therapeutic potential of targeting adenosine A2A receptors (A2ARs) is immense due to their broad expression in the body and central nervous system. The role of A2ARs in cardiovascular function, inflammation, sleep/wake behaviors, cognition, and other primary nervous system functions has been extensively studied. Numerous A2AR agonist and antagonist molecules are reported, many of which are currently in clinical trials or have already been approved for treatment. Allosteric modulators can selectively elicit a physiologic response only where and when the orthosteric ligand is released, which

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Orgován, Zoltán, György G. Ferenczy, and György M. Keserű. "Fragment-Based Approaches for Allosteric Metabotropic Glutamate Receptor (mGluR) Modulators." Current Topics in Medicinal Chemistry 19, no. 19 (2019): 1768–81. http://dx.doi.org/10.2174/1568026619666190808150039.

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Metabotropic glutamate receptors (mGluR) are members of the class C G-Protein Coupled Receptors (GPCR-s) and have eight subtypes. These receptors are responsible for a variety of functions in the central and peripheral nervous systems and their modulation has therapeutic utility in neurological and psychiatric disorders. It was previously established that selective orthosteric modulation of these receptors is challenging, and this stimulated the search for allosteric modulators. Fragment-Based Drug Discovery (FBDD) is a viable approach to find ligands binding at allosteric sites owing to their

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Wootten, Denise, and Laurence J. Miller. "Structural Basis for Allosteric Modulation of Class B G Protein–Coupled Receptors." Annual Review of Pharmacology and Toxicology 60, no. 1 (2020): 89–107. http://dx.doi.org/10.1146/annurev-pharmtox-010919-023301.

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Recent advances in our understanding of the structure and function of class B G protein–coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, t

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Bhagwanth, Swapna, Ram K. Mishra, and Rodney L. Johnson. "Development of peptidomimetic ligands of Pro-Leu-Gly-NH2 as allosteric modulators of the dopamine D2 receptor." Beilstein Journal of Organic Chemistry 9 (January 30, 2013): 204–14. http://dx.doi.org/10.3762/bjoc.9.24.

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A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH2 (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to establish that PLG binds to the D2 dopamine receptor at a site that is different from the orthosteric site, thus making PLG and its peptidomimetics allosteric modulators of the dopamine receptor. Through the design, synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam,

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Gasparini, F., and W. Spooren. "Allosteric Modulators for mGlu Receptors." Current Neuropharmacology 5, no. 3 (2007): 187–94. http://dx.doi.org/10.2174/157015907781695900.

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Abood, Mary E. "Allosteric Modulators: A Side Door." Journal of Medicinal Chemistry 59, no. 1 (2015): 42–43. http://dx.doi.org/10.1021/acs.jmedchem.5b01824.

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Orgován, Zoltán, György G. Ferenczy, and György M. Keserű. "The role of water and protein flexibility in the structure-based virtual screening of allosteric GPCR modulators: an mGlu5 receptor case study." Journal of Computer-Aided Molecular Design 33, no. 9 (2019): 787–97. http://dx.doi.org/10.1007/s10822-019-00224-w.

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Abstract Stabilizing unique receptor conformations, allosteric modulators of G-protein coupled receptors (GPCRs) might open novel treatment options due to their new pharmacological action, their enhanced specificity and selectivity in both binding and signaling. Ligand binding occurs at intrahelical allosteric sites and involves significant induced fit effects that include conformational changes in the local protein environment and water networks. Based on the analysis of available crystal structures of metabotropic glutamate receptor 5 (mGlu5) we investigated these effects in the binding of m

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Davey, Anna E., Katie Leach, Celine Valant, Arthur D. Conigrave, Patrick M. Sexton, and Arthur Christopoulos. "Positive and Negative Allosteric Modulators Promote Biased Signaling at the Calcium-Sensing Receptor." Endocrinology 153, no. 3 (2012): 1232–41. http://dx.doi.org/10.1210/en.2011-1426.

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The calcium-sensing receptor (CaSR) is a G protein-coupled receptor whose function can be allosterically modulated in a positive or negative manner by calcimimetics or calcilytics, respectively. Indeed, the second-generation calcimimetic, cinacalcet, has proven clinically useful in the treatment of chronic kidney disease patients with secondary hyperparathyroidism but is not widely used in earlier stages of renal disease due to the potential to predispose such patients to hypocalcaemia and hyperphosphatemia. The development of a biased CaSR ligand that is more selective for specific signaling

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Yuan, Jiayi, Chen Jiang, Junmei Wang, et al. "In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators." Molecules 27, no. 2 (2022): 453. http://dx.doi.org/10.3390/molecules27020453.

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Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-

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Bruder, Marjorie, Gina Polo, and Daniela B. B. Trivella. "Natural allosteric modulators and their biological targets: molecular signatures and mechanisms." Natural Product Reports 37, no. 4 (2020): 488–514. http://dx.doi.org/10.1039/c9np00064j.

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Jiang, Jason Y., Mulpuri Nagaraju, Rebecca C. Meyer та ін. "Extracellular Calcium Modulates Actions of Orthosteric and Allosteric Ligands on Metabotropic Glutamate Receptor 1α". Journal of Biological Chemistry 289, № 3 (2013): 1649–61. http://dx.doi.org/10.1074/jbc.m113.507665.

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Metabotropic glutamate receptor 1α (mGluR1α), a member of the family C G protein-coupled receptors, is emerging as a potential drug target for various disorders, including chronic neuronal degenerative diseases. In addition to being activated by glutamate, mGluR1α is also modulated by extracellular Ca2+. However, the underlying mechanism is unknown. Moreover, it has long been challenging to develop receptor-specific agonists due to homologies within the mGluR family, and the Ca2+-binding site(s) on mGluR1α may provide an opportunity for receptor-selective targeting by therapeutics. In the pres

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Reinecke, Bethany A., Huiqun Wang, and Yan Zhang. "Recent Advances in the Drug Discovery and Development of Dualsteric/ Bitopic Activators of G Protein-Coupled Receptors." Current Topics in Medicinal Chemistry 19, no. 26 (2019): 2378–92. http://dx.doi.org/10.2174/1568026619666191009164609.

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G protein-coupled receptors (GPCRs) represent the largest family of proteins targeted by drug design and discovery efforts. Of these efforts, the development of GPCR agonists is highly desirable, due to their therapeutic robust utility in treating diseases caused by deficient receptor signaling. One of the challenges in designing potent and selective GPCR agonists lies in the inability to achieve combined high binding affinity and subtype selectivity, due to the high homology between orthosteric sites among GPCR subtypes. To combat this difficulty, researchers have begun to explore the utility

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Li, Mengrong, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, and Jingjing Guo. "Understanding the Allosteric Modulation of PTH1R by a Negative Allosteric Modulator." Cells 12, no. 1 (2022): 41. http://dx.doi.org/10.3390/cells12010041.

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The parathyroid hormone type 1 receptor (PTH1R) acts as a canonical class B G protein-coupled receptor, regulating crucial functions including calcium homeostasis and bone formation. The identification and development of PTH1R non-peptide allosteric modulators have obtained widespread attention. It has been found that a negative allosteric modulator (NAM) could inhibit the activation of PTH1R, but the implied mechanism remains unclear. Herein, extensive molecular dynamics simulations together with multiple analytical approaches are utilized to unravel the mechanism of PTH1R allosteric inhibiti

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Fernández-Dueñas, Víctor, Mingcheng Qian, Josep Argerich, et al. "Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators." Molecules 25, no. 7 (2020): 1532. http://dx.doi.org/10.3390/molecules25071532.

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In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter’ systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu5R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel alloster

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Felsing, Daniel E., Manish K. Jain, and John A. Allen. "Advances in Dopamine D1 Receptor Ligands for Neurotherapeutics." Current Topics in Medicinal Chemistry 19, no. 16 (2019): 1365–80. http://dx.doi.org/10.2174/1568026619666190712210903.

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The dopamine D1 receptor (D1R) is essential for neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Not surprisingly, the D1R has been validated as a promising drug target for over 40 years and selective activation of this receptor may provide novel neurotherapeutics for neurodegenerative and neuropsychiatric disorders. Several pharmacokinetic challenges with previously identified small molecule D1R agonists have been recently overcome with the discovery and advancement of new ligands, including drug-like non-

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Matosiuk, Dariusz. "Potential Future of New Glutamate Agonists and Antagonists Development." Anti-Cancer Agents in Medicinal Chemistry 18, no. 4 (2018): 506–20. http://dx.doi.org/10.2174/1871520618666180404125041.

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Receptors of glutamic acid are known for over 30 years for their action and for about 20 years for their structure. Presence of at least three classes of ionotropic receptors was confirmed at the beginning of 80’. Recognition of the sequence and first cloning were done at the beginning of 90’. In 1994 ligand binding site was recognized at the junction of two subunits S1-S2 in the ligand-binding domain. Since then, many subtypes of ionotropic and metabotropic glutamate receptors were recognized, together with their localization and functions. In the meantime numerous orthosteric ligands, both a

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Bartuzi, Damian, Tomasz M. Wróbel, Agnieszka A. Kaczor, and Dariusz Matosiuk. "Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses." Current Topics in Medicinal Chemistry 20, no. 31 (2020): 2852–65. http://dx.doi.org/10.2174/1568026620666200601155451.

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Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is al

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Burger, Wessel A. C., Patrick M. Sexton, Arthur Christopoulos, and David M. Thal. "Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors." Journal of General Physiology 150, no. 10 (2018): 1360–72. http://dx.doi.org/10.1085/jgp.201711979.

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Recent breakthroughs and developments in structural biology have led to a spate of crystal structures for G protein–coupled receptors (GPCRs). This is the case for the muscarinic acetylcholine receptors (mAChRs) where inactive-state structures for four of the five subtypes and two active-state structures for one subtype are available. These mAChR crystal structures have provided new insights into receptor mechanisms, dynamics, and allosteric modulation. This is highly relevant to the mAChRs given that these receptors are an exemplar model system for the study of GPCR allostery. Allosteric mech

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Sebastian, Roy. "Allosteric modulators in CNS disorders: review." Journal of Psychology & Clinical Psychiatry 9, no. 6 (2018): 587–89. http://dx.doi.org/10.15406/jpcpy.2018.09.00592.

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