Journal articles on the topic 'Allosteric ligands'
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1
Kuznetsov, Aleksei, and Jaak Järv. "Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit." Open Life Sciences 4, no. 2 (June 1, 2009): 131–41. http://dx.doi.org/10.2478/s11535-009-0012-6.
Abstract:
AbstractProtein kinase A (cAMP dependent protein kinase catalytic subunit, EC 2.7.11.11) binds simultaneously ATP and a phosphorylatable peptide. These structurally dissimilar allosteric ligands influence the binding effectiveness of each other. The same situation is observed with substrate congeners, which reversibly inhibit the enzyme. In this review these allosteric effects are quantified using the interaction factor, which compares binding effectiveness of ligands with the free enzyme and the pre-loaded enzyme complex containing another ligand. This analysis revealed that the allosteric effect depends upon structure of the interacting ligands, and the principle “better binding: stronger allostery” observed can be formalized in terms of linear free-energy relationships, which point to similar mechanism of the allosteric interaction between the enzyme-bound substrates and/or inhibitor molecules. On the other hand, the type of effect is governed by ligand binding effectiveness and can be inverted from positive allostery to negative allostery if we move from effectively binding ligands to badly binding compounds. Thus the outcome of the allostery in this monomeric enzyme is the same as defined by classical theories for multimeric enzymes: making the enzyme response more efficient if appropriate ligands bind.
2
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 (October 26, 2004): 873–77. http://dx.doi.org/10.1042/bst0320873.
Abstract:
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 validation of allosteric ligands.
3
Köhler, C., G. Carlström, A. Gunnarsson, U. Weininger, S. Tångefjord, V. Ullah, M. Lepistö, et al. "Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor." Science Advances 6, no. 29 (July 2020): eabb5277. http://dx.doi.org/10.1126/sciadv.abb5277.
Abstract:
Allosteric communication within proteins is a hallmark of biochemical signaling, but the dynamic transmission pathways remain poorly characterized. We combined NMR spectroscopy and surface plasmon resonance to reveal these pathways and quantify their energetics in the glucocorticoid receptor, a transcriptional regulator controlling development, metabolism, and immune response. Our results delineate a dynamic communication network of residues linking the ligand-binding pocket to the activation function-2 interface, where helix 12, a switch for transcriptional activation, exhibits ligand- and coregulator-dependent dynamics coupled to graded activation. The allosteric free energy responds to variations in ligand structure: subtle changes gradually tune allostery while preserving the transmission pathway, whereas substitution of the entire pharmacophore leads to divergent allosteric control by apparently rewiring the communication network. Our results provide key insights that should aid in the design of mechanistically differentiated ligands.
4
Mitchell, Michael R., Tsvi Tlusty, and Stanislas Leibler. "Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings." Proceedings of the National Academy of Sciences 113, no. 40 (September 21, 2016): E5847—E5855. http://dx.doi.org/10.1073/pnas.1609462113.
Abstract:
In many proteins, especially allosteric proteins that communicate regulatory states from allosteric to active sites, structural deformations are functionally important. To understand these deformations, dynamical experiments are ideal but challenging. Using static structural information, although more limited than dynamical analysis, is much more accessible. Underused for protein analysis, strain is the natural quantity for studying local deformations. We calculate strain tensor fields for proteins deformed by ligands or thermal fluctuations using crystal and NMR structure ensembles. Strains—primarily shears—show deformations around binding sites. These deformations can be induced solely by ligand binding at distant allosteric sites. Shears reveal quasi-2D paths of mechanical coupling between allosteric and active sites that may constitute a widespread mechanism of allostery. We argue that strain—particularly shear—is the most appropriate quantity for analysis of local protein deformations. This analysis can reveal mechanical and biological properties of many proteins.
5
Abrusán, György, and Joseph A. Marsh. "Ligand-Binding-Site Structure Shapes Allosteric Signal Transduction and the Evolution of Allostery in Protein Complexes." Molecular Biology and Evolution 36, no. 8 (April 19, 2019): 1711–27. http://dx.doi.org/10.1093/molbev/msz093.
Abstract:
Abstract The structure of ligand-binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multichain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologs, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand-binding-site structure shapes allosteric signal transduction pathways, and whether the structural similarity of binding sites influences the evolution of allostery. Our analyses show that: 1) allostery is more frequent among MBS complexes than in SBS complexes, particularly in homomers; 2) in MBS homomers, semirigid communities and critical residues frequently connect interfaces and thus they are characterized by signal transduction pathways that cross protein–protein interfaces, whereas SBS homomers usually not; 3) ligand binding alters community structure differently in MBS and SBS homomers; and 4) except MBS homomers, allosteric proteins are more likely to have homologs with similar binding site than nonallosteric proteins, suggesting that binding site similarity is an important factor driving the evolution of allostery.
6
Gao, Zhan-Guo, Kiran S. Toti, Ryan Campbell, R. Rama Suresh, Huijun Yang, and Kenneth A. Jacobson. "Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands." Cells 9, no. 5 (May 12, 2020): 1200. http://dx.doi.org/10.3390/cells9051200.
Abstract:
Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A2A adenosine receptor (A2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed Ki binding values consistent with KB values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(N,N-hexamethylene)amiloride (HMA) were 9–100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric A2AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [3H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different A2AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate.
7
Abrusán, György, David B. Ascher, and Michael Inouye. "Known allosteric proteins have central roles in genetic disease." PLOS Computational Biology 18, no. 2 (February 9, 2022): e1009806. http://dx.doi.org/10.1371/journal.pcbi.1009806.
Abstract:
Allostery is a form of protein regulation, where ligands that bind sites located apart from the active site can modify the activity of the protein. The molecular mechanisms of allostery have been extensively studied, because allosteric sites are less conserved than active sites, and drugs targeting them are more specific than drugs binding the active sites. Here we quantify the importance of allostery in genetic disease. We show that 1) known allosteric proteins are central in disease networks, contribute to genetic disease and comorbidities much more than non-allosteric proteins, and there is an association between being allosteric and involvement in disease; 2) they are enriched in many major disease types like hematopoietic diseases, cardiovascular diseases, cancers, diabetes, or diseases of the central nervous system; 3) variants from cancer genome-wide association studies are enriched near allosteric proteins, indicating their importance to polygenic traits; and 4) the importance of allosteric proteins in disease is due, at least partly, to their central positions in protein-protein interaction networks, and less due to their dynamical properties.
8
Kenakin, Terry P. "Ligand Detection in the Allosteric World." Journal of Biomolecular Screening 15, no. 2 (January 19, 2010): 119–30. http://dx.doi.org/10.1177/1087057109357789.
Abstract:
Historically, traditional screening for ligands has been optimized to detect standard orthosteric agonists and antagonists. However, with increasing emphasis on cellular functional screens, more allosteric ligands are being discovered as potential drugs. In addition, there are theoretical reasons (increased selectivity, better control of physiological systems, separate control of affinity and efficacy) allosteric ligands may be preferred therapeutic chemical targets. These factors may make it desirable to design high-throughput screens to specifically detect functionally allosteric ligands. This article discusses the unique features of allosteric ligands as drugs as well as the special conditions that should be considered to optimize a high-throughput screen toward the detection of allosteric drugs. Finally, the likelihood of detecting allosteric ligands that have direct effects on cells (either conventional agonism or functionally selective effects) is discussed as well as the optimization of detection of such ligands in screening assays.
9
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 (October 21, 2019): 1768–81. http://dx.doi.org/10.2174/1568026619666190808150039.
Abstract:
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 limited size and interactions. However, it was also observed that the structure-activity relationship of allosteric modulators is often sharp and inconsistent. This can be attributed to the characteristics of the allosteric binding site of mGluRs that is a water channel where ligand binding is accompanied with induced fit and interference with the water network, both playing a role in receptor activation. In this review, we summarize fragment-based drug discovery programs on mGluR allosteric modulators and their contribution identifying of new mGluR ligands with better activity and selectivity.
10
White, Alex D., Fei Fang, Frédéric G. Jean-Alphonse, Lisa J. Clark, Hyun-Jung An, Hongda Liu, Yang Zhao, et al. "Ca2+ allostery in PTH-receptor signaling." Proceedings of the National Academy of Sciences 116, no. 8 (February 4, 2019): 3294–99. http://dx.doi.org/10.1073/pnas.1814670116.
Abstract:
The parathyroid hormone (PTH) and its related peptide (PTHrP) activate PTH receptor (PTHR) signaling, but only the PTH sustains GS-mediated adenosine 3′,5′-cyclic monophosphate (cAMP) production after PTHR internalization into early endosomes. The mechanism of this unexpected behavior for a G-protein–coupled receptor is not fully understood. Here, we show that extracellular Ca2+ acts as a positive allosteric modulator of PTHR signaling that regulates sustained cAMP production. Equilibrium and kinetic studies of ligand-binding and receptor activation reveal that Ca2+ prolongs the residence time of ligands on the receptor, thus, increasing both the duration of the receptor activation and the cAMP signaling. We further find that Ca2+ allostery in the PTHR is strongly affected by the point mutation recently identified in the PTH (PTHR25C) as a new cause of hypocalcemia in humans. Using high-resolution and mass accuracy mass spectrometry approaches, we identified acidic clusters in the receptor’s first extracellular loop as key determinants for Ca2+ allosterism and endosomal cAMP signaling. These findings coupled to defective Ca2+ allostery and cAMP signaling in the PTHR by hypocalcemia-causing PTHR25C suggest that Ca2+ allostery in PTHR signaling may be involved in primary signaling processes regulating calcium homeostasis.
11
Burford, Neil T., Tom Wehrman, Daniel Bassoni, Jonathan O’Connell, Martyn Banks, Litao Zhang, and Andrew Alt. "Identification of Selective Agonists and Positive Allosteric Modulators for µ- and δ-Opioid Receptors from a Single High-Throughput Screen." Journal of Biomolecular Screening 19, no. 9 (July 21, 2014): 1255–65. http://dx.doi.org/10.1177/1087057114542975.
Abstract:
Hetero-oligomeric complexes of G protein–coupled receptors (GPCRs) may represent novel therapeutic targets exhibiting different pharmacology and tissue- or cell-specific site of action compared with receptor monomers or homo-oligomers. An ideal tool for validating this concept pharmacologically would be a hetero-oligomer selective ligand. We set out to develop and execute a 1536-well high-throughput screen of over 1 million compounds to detect potential hetero-oligomer selective ligands using a β-arrestin recruitment assay in U2OS cells coexpressing recombinant µ- and δ-opioid receptors. Hetero-oligomer selective ligands may bind to orthosteric or allosteric sites, and we might anticipate that the formation of hetero-oligomers may provide novel allosteric binding pockets for ligand binding. Therefore, our goal was to execute the screen in such a way as to identify positive allosteric modulators (PAMs) as well as agonists for µ, δ, and hetero-oligomeric receptors. While no hetero-oligomer selective ligands were identified (based on our selection criteria), this single screen did identify numerous µ- and δ-selective agonists and PAMs as well as nonselective agonists and PAMs. To our knowledge, these are the first µ- and δ-opioid receptor PAMs described in the literature.
12
Jakubik, Jan, and Esam E. El-Fakahany. "Current Advances in Allosteric Modulation of Muscarinic Receptors." Biomolecules 10, no. 2 (February 18, 2020): 325. http://dx.doi.org/10.3390/biom10020325.
Abstract:
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, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.
13
Thirumalai, D., and Changbong Hyeon. "Signalling networks and dynamics of allosteric transitions in bacterial chaperonin GroEL: implications for iterative annealing of misfolded proteins." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (May 7, 2018): 20170182. http://dx.doi.org/10.1098/rstb.2017.0182.
Abstract:
Signal transmission at the molecular level in many biological complexes occurs through allosteric transitions. Allostery describes the responses of a complex to binding of ligands at sites that are spatially well separated from the binding region. We describe the structural perturbation method, based on phonon propagation in solids, which can be used to determine the signal-transmitting allostery wiring diagram (AWD) in large but finite-sized biological complexes. Application to the bacterial chaperonin GroEL–GroES complex shows that the AWD determined from structures also drives the allosteric transitions dynamically. From both a structural and dynamical perspective these transitions are largely determined by formation and rupture of salt-bridges. The molecular description of allostery in GroEL provides insights into its function, which is quantitatively described by the iterative annealing mechanism. Remarkably, in this complex molecular machine, a deep connection is established between the structures, reaction cycle during which GroEL undergoes a sequence of allosteric transitions, and function, in a self-consistent manner. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.
14
Motlagh, Hesam N., Jing Li, E. Brad Thompson, and Vincent J. Hilser. "Interplay between allostery and intrinsic disorder in an ensemble." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 975–80. http://dx.doi.org/10.1042/bst20120163.
Abstract:
Allostery is a biological phenomenon of critical importance in metabolic regulation and cell signalling. The fundamental premise of classical models that describe allostery is that structure mediates ‘action at a distance’. Recently, this paradigm has been challenged by the enrichment of IDPs (intrinsically disordered proteins) or ID (intrinsically disordered) segments in transcription factors and signalling pathways of higher organisms, where an allosteric response from external signals is requisite for regulated function. This observation strongly suggests that IDPs elicit the capacity for finely tunable allosteric regulation. Is there a set of transferable ground rules that reconcile these disparate allosteric phenomena? We focus on findings from the human GR (glucocorticoid receptor) which is a nuclear transcription factor in the SHR (steroid hormone receptor) family. GR contains an intrinsically disordered NTD (N-terminal domain) that is obligatory for transcription activity. Different GR translational isoforms have various lengths of NTD and by studying these isoforms we found that the full-length ID NTD consists of two thermodynamically distinct coupled regions. The data are interpreted in the context of an EAM (ensemble allosteric model) that considers only the intrinsic and measurable energetics of allosteric systems. Expansion of the EAM is able to reconcile the paradox that ligands for SHRs can be agonists and antagonists in a cell-context-dependent manner. These findings suggest a mechanism by which SHRs in particular, and IDPs in general, may have evolved to couple thermodynamically distinct ID segments. The ensemble view of allostery that is illuminated provides organizing principles to unify the description of all allosteric systems and insight into ‘how’ allostery works.
15
Atkins, William M. "NON-MICHAELIS-MENTEN KINETICS IN CYTOCHROME P450-CATALYZED REACTIONS." Annual Review of Pharmacology and Toxicology 45, no. 1 (September 22, 2005): 291–310. http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100004.
Abstract:
The cytochrome P450 monooxygenases (CYPs) are the dominant enzyme system responsible for xenobiotic detoxification and drug metabolism. Several CYP isoforms exhibit non-Michaelis-Menten, or “atypical,” steady state kinetic patterns. The allosteric kinetics confound prediction of drug metabolism and drug-drug interactions, and they challenge the theoretical paradigms of allosterism. Both homotropic and heterotropic ligand effects are now widely documented. It is becoming apparent that multiple ligands can simultaneously bind within the active sites of individual CYPs, and the kinetic parameters change with ligand occupancy. In fact, the functional effect of any specific ligand as an activator or inhibitor can be substrate dependent. Divergent approaches, including kinetic modeling and X-ray crystallography, are providing new information about how multiple ligand binding yields complex CYP kinetics.
16
Jiao, Wanting. "Computational investigations of allostery in aromatic amino acid biosynthetic enzymes." Biochemical Society Transactions 49, no. 1 (February 5, 2021): 415–29. http://dx.doi.org/10.1042/bst20200741.
Abstract:
Allostery, in which binding of ligands to remote sites causes a functional change in the active sites, is a fascinating phenomenon observed in enzymes. Allostery can occur either with or without significant conformational changes in the enzymes, and the molecular basis of its mechanism can be difficult to decipher using only experimental techniques. Computational tools for analyzing enzyme sequences, structures, and dynamics can provide insights into the allosteric mechanism at the atomic level. Combining computational and experimental methods offers a powerful strategy for the study of enzyme allostery. The aromatic amino acid biosynthesis pathway is essential in microorganisms and plants. Multiple enzymes involved in this pathway are sensitive to feedback regulation by pathway end products and are known to use allostery to control their activities. To date, four enzymes in the aromatic amino acid biosynthesis pathway have been computationally investigated for their allosteric mechanisms, including 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase, anthranilate synthase, chorismate mutase, and tryptophan synthase. Here we review the computational studies and findings on the allosteric mechanisms of these four enzymes. Results from these studies demonstrate the capability of computational tools and encourage future computational investigations of allostery in other enzymes of this pathway.
17
Matosiuk, Dariusz. "Potential Future of New Glutamate Agonists and Antagonists Development." Anti-Cancer Agents in Medicinal Chemistry 18, no. 4 (July 17, 2018): 506–20. http://dx.doi.org/10.2174/1871520618666180404125041.
Abstract:
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 agonists and antagonists were developed especially for NMDA ion channels. Their usefulness as drugs was rather low, due to the involvement in the excitatory tract. More interest was focused on metabotropic receptors, which are GPSR’s and can be modulated both by orthosteric and allosteric modulators. It seems like allosterism could be considered as promising future for glutamate receptors and ion channels, especially when first allosteric negative modulators of the mGluR2 went close into the clinical trial.
18
de Vries, Rens M. J. M., Femke A. Meijer, Richard G. Doveston, Iris A. Leijten-van de Gevel, and Luc Brunsveld. "Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt." Proceedings of the National Academy of Sciences 118, no. 6 (February 3, 2021): e2021287118. http://dx.doi.org/10.1073/pnas.2021287118.
Abstract:
Cooperative ligand binding is an important phenomenon in biological systems where ligand binding influences the binding of another ligand at an alternative site of the protein via an intramolecular network of interactions. The underlying mechanisms behind cooperative binding remain poorly understood, primarily due to the lack of structural data of these ternary complexes. Using time-resolved fluorescence resonance energy transfer (TR-FRET) studies, we show that cooperative ligand binding occurs for RORγt, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of RORγt simultaneously bound to various orthosteric and allosteric ligands. The presence of the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5. Additional molecular dynamics simulations revealed the unusual mechanism behind this clamping motion, with Ala355 shifting between helix 4 and 5. The orthosteric RORγt agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists.
19
Fernández-Dueñas, Víctor, Mingcheng Qian, Josep Argerich, Carolina Amaral, Martijn D. P. Risseeuw, Serge Van Calenbergh, and Francisco Ciruela. "Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators." Molecules 25, no. 7 (March 27, 2020): 1532. http://dx.doi.org/10.3390/molecules25071532.
Abstract:
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 allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu5Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu5R allosteric modulators.
20
Whitehurst, Charles E., Naim Nazef, D. Allen Annis, Yongmin Hou, Denise M. Murphy, Peter Spacciapoli, Zhiping Yao, et al. "Discovery and Characterization of Orthosteric and Allosteric Muscarinic M2 Acetylcholine Receptor Ligands by Affinity Selection-Mass Spectrometry." Journal of Biomolecular Screening 11, no. 2 (December 16, 2005): 194–207. http://dx.doi.org/10.1177/1087057105284340.
Abstract:
Screening assays using target-based affinity selection coupled with high-sensitivity detection technologies to identify small-molecule hits from chemical libraries can provide a useful discovery approach that complements traditional assay systems. Affinity selection-mass spectrometry (AS-MS) is one such methodology that holds promise for providing selective and sensitive high-throughput screening platforms. Although AS-MS screening platforms have been used to discover small-molecule ligands of proteins from many target families, they have not yet been used routinely to screen integral membrane proteins. The authors present a proof-of-concept study using size exclusion chromatography coupled to AS-MS to perform a primary screen for small-molecule ligands of the purified muscarinic M2 acetylcholine receptor, a G-protein-coupled receptor. AS-MS is used to characterize the binding mechanisms of 2 newly discovered ligands. NGD-3350 is a novel M2-specific orthosteric antagonist of M2 function. NGD-3366 is an allosteric ligand with binding properties similar to the allosteric antagonist W-84, which decreases the dissociation rate of N-methyl-scopolamine from the M2 receptor. Binding properties of the ligands discerned from AS-MS assays agree with those from in vitro biochemical assays. The authors conclude that when used with appropriate small-molecule libraries, AS-MS may provide a useful high-throughput assay system for the discovery and characterization of all classes of integral membrane protein ligands, including allosteric modulators.
21
Harini, K., S. Jayashree, Vikas Tiwari, Sneha Vishwanath, and Ramanathan Sowdhamini. "Ligand Docking Methods to Recognize Allosteric Inhibitors for G-Protein-Coupled Receptors." Bioinformatics and Biology Insights 15 (January 2021): 117793222110377. http://dx.doi.org/10.1177/11779322211037769.
Abstract:
G-protein-coupled receptors (GPCRs) are membrane proteins which play an important role in many cellular processes and are excellent drug targets. Despite the existence of several US Food and Drug Administration (FDA)-approved GPCR-targeting drugs, there is a continuing challenge of side effects owing to the nonspecific nature of drug binding. We have investigated the diversity of the ligand binding site for this class of proteins against their cognate ligands using computational docking, even if their structures are known already in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site with better score than the binding at the conservative site. Interestingly, amino acid residues at such allosteric binding site are not conserved across GPCR subfamilies. Such a computational approach can assist in the prediction of specific allosteric binders for GPCRs.
22
Singh, Khuraijam Dhanachandra, Zaira P. Jara, Terri Harford, Prasenjit Prasad Saha, Triveni R. Pardhi, Russell Desnoyer, and Sadashiva S. Karnik. "Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers." Proceedings of the National Academy of Sciences 118, no. 33 (August 11, 2021): e2019126118. http://dx.doi.org/10.1073/pnas.2019126118.
Abstract:
While orthosteric ligands of the angiotensin II (AngII) type 1 receptor (AT1R) are available for clinical and research applications, allosteric ligands are not known for this important G protein-coupled receptor (GPCR). Allosteric ligands are useful tools to modulate receptor pharmacology and subtype selectivity. Here, we report AT1R allosteric ligands for a potential application to block autoimmune antibodies. The epitope of autoantibodies for AT1R is outside the orthosteric pocket in the extracellular loop 2. A molecular dynamics simulation study of AT1R structure reveals the presence of a druggable allosteric pocket encompassing the autoantibody epitope. Small molecule binders were then identified for this pocket using structure-based high-throughput virtual screening. The top 18 hits obtained inhibited the binding of antibody to AT1R and modulated agonist-induced calcium response of AT1R. Two compounds out of 18 studied in detail exerted a negative allosteric modulator effect on the functions of the natural agonist AngII. They blocked antibody-enhanced calcium response and reactive oxygen species production in vascular smooth muscle cells as well as AngII-induced constriction of blood vessels, demonstrating their efficacy in vivo. Our study thus demonstrates the feasibility of discovering inhibitors of the disease-causing autoantibodies for GPCRs. Specifically, for AT1R, we anticipate development of more potent allosteric drug candidates for intervention in autoimmune maladies such as preeclampsia, bilateral adrenal hyperplasia, and the rejection of organ transplants.
23
Mazzolari, Angelica, Silvia Gervasoni, Alessandro Pedretti, Laura Fumagalli, Rosanna Matucci, and Giulio Vistoli. "Repositioning Dequalinium as Potent Muscarinic Allosteric Ligand by Combining Virtual Screening Campaigns and Experimental Binding Assays." International Journal of Molecular Sciences 21, no. 17 (August 19, 2020): 5961. http://dx.doi.org/10.3390/ijms21175961.
Abstract:
Structure-based virtual screening is a truly productive repurposing approach provided that reliable target structures are available. Recent progresses in the structural resolution of the G-Protein Coupled Receptors (GPCRs) render these targets amenable for structure-based repurposing studies. Hence, the present study describes structure-based virtual screening campaigns with a view to repurposing known drugs as potential allosteric (and/or orthosteric) ligands for the hM2 muscarinic subtype which was indeed resolved in complex with an allosteric modulator thus allowing a precise identification of this binding cavity. First, a docking protocol was developed and optimized based on binding space concept and enrichment factor optimization algorithm (EFO) consensus approach by using a purposely collected database including known allosteric modulators. The so-developed consensus models were then utilized to virtually screen the DrugBank database. Based on the computational results, six promising molecules were selected and experimentally tested and four of them revealed interesting affinity data; in particular, dequalinium showed a very impressive allosteric modulation for hM2. Based on these results, a second campaign was focused on bis-cationic derivatives and allowed the identification of other two relevant hM2 ligands. Overall, the study enhances the understanding of the factors governing the hM2 allosteric modulation emphasizing the key role of ligand flexibility as well as of arrangement and delocalization of the positively charged moieties.
24
Micucci, Joseph A., Parvathi Kamath, Anuja Khan, Paul E. Bock, and Sriram Krishnaswamy. "Long-Range Allosteric Linkage Between Exosites Reciprocally Regulates the Zymogenicity of Prothrombin Derivatives." Blood 126, no. 23 (December 3, 2015): 122. http://dx.doi.org/10.1182/blood.v126.23.122.122.
Abstract:
Abstract The binding of ligands to anion binding exosite I (ABEI) and exosite II (ABEII) on prothrombin (II) derivatives plays an integral role in regulating their function. These exosites are located on opposite faces of the proteinase domain and exhibit unique binding specificities. Fragment 1.2 (F12) binds to ABEII and acts as a zymogen-promoting allosteric ligand. Conversely, Na+ and active site ligands stabilize the proteinase state. Here, we investigated the allosteric linkage between ABEI and the Na+ binding site, active site or ABEII using multiple ABEI ligands and prothrombin derivatives differentially poised along the zymogen to proteinase continuum. Prethrombin 2 (P2) represents the most zymogen-like state that differs from thrombin (IIa) because it is not cleaved at the R320 site. To mimic the zymogen-like character of P2 in a cleaved IIa molecule, residues responsible for N-terminal insertion and proteinase formation (IVE) were swapped with TAT to produce IIaTAT, a mutant with vastly diminished proteolytic activity. Alanine was substituted with the catalytic serine residue in IIa (IIaS195A) to represent the proteinase without a ligand at its active site. The thermodynamics of interactions between the thrombin inhibitor and ABEI ligand hirugen (Hir) and the various reference states was assessed using isothermal titration calorimetry (ITC). Titration of Hir into P2, IIaTAT or IIaS195A revealed thermodynamically more favorable binding to proteinase-like IIaS195A in comparison to zymogen-like P2 or IIaTAT. Binding of Hir to IIaS195A was affected by the concentration of Na+ at constant ionic strength. Global analysis done in the presence of increasing concentrations of Na+ revealed a 5-fold increase in Hir binding affinity when IIaS195A is ligated with Na+; demonstrating positive allosteric linkage between ABEI and Na+ binding. Using a truncated Staphylocoagulase variant that binds ABEI without N-terminus insertion (SC13-325), we found that SC13-325 binding alone promoted active site opening and fluorescent inhibitor incorporation in zymogen-like P2. These data reinforce the observation that ABEI ligands promote a proteinase-like state in prothrombin derivatives through positive allosteric linkage with the Na+ binding and active sites. Interestingly, inhibitor incorporation and ITC studies both showed that SC13-325 interacts poorly with II, but strongly with P2 despite both species being zymogens. These findings imply that the ABEII ligand F12, which is produced upon cleavage of II at R271 to form P2, may display negative allosteric linkage with ABEI. Titration of SC13-325 into pre-formed complexes of P2/F12 revealed a drastic reduction in affinity of SC13-325 for P2 when F12 is bound to ABEII. Thus, F12 binding at ABEII negatively affects ABEI binding. Further studies used soluble thrombomodulin (sTM) as the most physiologically pertinent ligand for ABEI. ITC and global analysis of the binding of F12 to P2 in the presence of different concentrations of sTM revealed a ~1200-fold decrease in binding affinity and enthalpy for either the binding of F12 to P2 bound to sTM or the binding of sTM to P2 bound to F12. These data illustrate the strong negative linkage associated with the binding of protein ligands to ABEI and ABEII which yields the appearance of competitive and mutually exclusive binding at the two sites despite the fact that they are on opposite sides of the proteinase domain. Allosteric linkage between ligand binding at the two exosites is centered on the ability of F12 binding to ABEII and favor zymogen-like forms and ligand binding to ABEI to favor proteinase-like forms. Thus, allosteric linkage among exosites is vital to the interconversion of prothrombin species along the zymogen to proteinase spectrum. These ligand-dependent conformational shifts and associated changes in function are likely to greatly contribute to the dynamic roles that IIa plays during coagulation. Disclosures No relevant conflicts of interest to declare.
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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 (August 2019): 2019–37. http://dx.doi.org/10.4155/fmc-2019-0005.
Abstract:
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 orthosteric ligands. This review aims to give an overview of the CB1 and CB2 receptor allosteric modulators highlighting the structure–activity relationship and pharmacological profile of each classes, and their future promise.
26
Wu, Feng-Jie, Lisa M. Williams, Alaa Abdul-Ridha, Avanka Gunatilaka, Tasneem M. Vaid, Martina Kocan, Alice R. Whitehead, et al. "Probing the correlation between ligand efficacy and conformational diversity at the α1A-adrenoreceptor reveals allosteric coupling of its microswitches." Journal of Biological Chemistry 295, no. 21 (April 17, 2020): 7404–17. http://dx.doi.org/10.1074/jbc.ra120.012842.
Abstract:
G protein–coupled receptors (GPCRs) use a series of conserved microswitches to transmit signals across the cell membrane via an allosteric network encompassing the ligand-binding site and the G protein-binding site. Crystal structures of GPCRs provide snapshots of their inactive and active states, but poorly describe the conformational dynamics of the allosteric network that underlies GPCR activation. Here, we analyzed the correlation between ligand binding and receptor conformation of the α1A-adrenoreceptor, a GPCR that stimulates smooth muscle contraction in response to binding noradrenaline. NMR of [13CϵH3]methionine-labeled α1A-adrenoreceptor variants, each exhibiting differing signaling capacities, revealed how different classes of ligands modulate the conformational equilibria of this receptor. [13CϵH3]Methionine residues near the microswitches exhibited distinct states that correlated with ligand efficacies, supporting a conformational selection mechanism. We propose that allosteric coupling among the microswitches controls the conformation of the α1A-adrenoreceptor and underlies the mechanism of ligand modulation of GPCR signaling in cells.
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Żuk, Justyna, Damian Bartuzi, Przemysław Miszta, and Agnieszka A. Kaczor. "The Role of Lipids in Allosteric Modulation of Dopamine D2 Receptor—In Silico Study." Molecules 27, no. 4 (February 16, 2022): 1335. http://dx.doi.org/10.3390/molecules27041335.
Abstract:
The dopamine D2 receptor, belonging to the class A G protein-coupled receptors (GPCRs), is an important drug target for several diseases, including schizophrenia and Parkinson’s disease. The D2 receptor can be activated by the natural neurotransmitter dopamine or by synthetic ligands, which in both cases leads to the receptor coupling with a G protein. In addition to receptor modulation by orthosteric or allosteric ligands, it has been shown that lipids may affect the behaviour of membrane proteins. We constructed a model of a D2 receptor with a long intracellular loop (ICL3) coupled with Giα1 or Giα2 proteins, embedded in a complex asymmetric membrane, and simulated it in complex with positive, negative or neutral allosteric ligands. In this study, we focused on the influence of ligand binding and G protein coupling on the membrane–receptor interactions. We show that there is a noticeable interplay between the cell membrane, G proteins, D2 receptor and its modulators.
28
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 (November 2, 2018): 2323–38. http://dx.doi.org/10.1042/cs20180374.
Abstract:
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 clinical trials; however, recent failures due to lack of efficacy or adverse effects indicate a need for a better understanding of the functional consequences of mGlu5 allosteric modulation. Biased agonism is an interrelated phenomenon to allosterism, describing how different ligands acting through the same receptor can differentially influence signaling to distinct transducers and pathways. Emerging evidence demonstrates that allosteric modulators can induce biased pharmacology at the level of intrinsic agonism as well as through differential modulation of orthosteric agonist-signaling pathways. Here, we present key considerations in the discovery and development of mGlu5 allosteric modulators and the opportunities and pitfalls offered by biased agonism and modulation.
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Hryhorowicz, Kaczmarek-Ryś, Andrzejewska, Staszak, Hryhorowicz, Korcz, and Słomski. "Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities." International Journal of Molecular Sciences 20, no. 23 (November 22, 2019): 5874. http://dx.doi.org/10.3390/ijms20235874.
Abstract:
The cannabinoid receptor type 1 (CB1R), a G protein-coupled receptor (GPCR), plays an essential role in the control of many physiological processes such as hunger, memory loss, gastrointestinal activity, catalepsy, fear, depression, and chronic pain. Therefore, it is an attractive target for drug discovery to manage pain, neurodegenerative disorders, obesity, and substance abuse. However, the psychoactive adverse effects, generated by CB1R activation in the brain, limit the use of the orthosteric CB1R ligands as drugs. The discovery of CB1R allosteric modulators during the last decade provided new tools to target the CB1R. Moreover, application of the site-directed mutagenesis in combination with advanced physical methods, especially X-ray crystallography and computational modeling, has opened new horizons for understanding the complexity of the structure, function, and activity of cannabinoid receptors. In this paper, we present the latest advances in research on the CB1R, its allosteric modulation and allosteric ligands, and their translational potential. We focused on structural essentials of the cannabinoid 1 receptor- ligand (drug) interactions, as well as modes of CB1R signaling regulation.
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Chen, Amy N. Y., Daniel T. Malone, Kavita Pabreja, Patrick M. Sexton, Arthur Christopoulos, and Meritxell Canals. "Detection and Quantification of Allosteric Modulation of Endogenous M4 Muscarinic Acetylcholine Receptor Using Impedance-Based Label-Free Technology in a Neuronal Cell Line." Journal of Biomolecular Screening 20, no. 5 (December 22, 2014): 646–54. http://dx.doi.org/10.1177/1087057114563025.
Abstract:
Allosteric modulators of G protein–coupled receptors have the potential to achieve greater receptor subtype selectivity compared with ligands targeting the orthosteric site of this receptor family. However, the high attrition rate in GPCR drug discovery programs has highlighted the need to better characterize lead compounds in terms of their allosteric action, as well as the signals they elicit. Recently, the use of label-free technologies has been proposed as an approach to overcome some limitations of endpoint-based assays and detect global changes in the ligand-stimulated cell. In this study, we assessed the ability of an impedance-based label-free technology, xCELLigence, to detect allosteric modulation in a neuronal cell line natively expressing rodent M4 muscarinic acetylcholine receptors. We were able to demonstrate that positive allosteric modulation of the endogenous M4 muscarinic acetylcholine receptor can be detected using this technology. Importantly, the allosteric parameters estimated from the label-free approach are comparable to those estimated from endpoint-based assays.
31
Chéron, Jean-Baptiste, Amanda Soohoo, Yi Wang, Jérôme Golebiowski, Serge Antonczak, Peihua Jiang, and Sébastien Fiorucci. "Conserved Residues Control the T1R3-Specific Allosteric Signaling Pathway of the Mammalian Sweet-Taste Receptor." Chemical Senses 44, no. 5 (March 20, 2019): 303–10. http://dx.doi.org/10.1093/chemse/bjz015.
Abstract:
Abstract Mammalian sensory systems detect sweet taste through the activation of a single heteromeric T1R2/T1R3 receptor belonging to class C G-protein-coupled receptors. Allosteric ligands are known to interact within the transmembrane domain, yet a complete view of receptor activation remains elusive. By combining site-directed mutagenesis with computational modeling, we investigate the structure and dynamics of the allosteric binding pocket of the T1R3 sweet-taste receptor in its apo form, and in the presence of an allosteric ligand, cyclamate. A novel positively charged residue at the extracellular loop 2 is shown to interact with the ligand. Molecular dynamics simulations capture significant differences in the behavior of a network of conserved residues with and without cyclamate, although they do not directly interact with the allosteric ligand. Structural models show that they adopt alternate conformations, associated with a conformational change in the transmembrane region. Site-directed mutagenesis confirms that these residues are unequivocally involved in the receptor function and the allosteric signaling mechanism of the sweet-taste receptor. Similar to a large portion of the transmembrane domain, they are highly conserved among mammals, suggesting an activation mechanism that is evolutionarily conserved. This work provides a structural basis for describing the dynamics of the receptor, and for the rational design of new sweet-taste modulators.
32
Root-Bernstein, Churchill, Turke, Subhramanyam, and Labahn. "Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities." International Journal of Molecular Sciences 20, no. 17 (August 24, 2019): 4137. http://dx.doi.org/10.3390/ijms20174137.
Abstract:
Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action.
33
Homsher, Michelle F., Douglas C. Beshore, Jason Cassaday, Brian Squadroni, Elizabeth Mohammed, Michelle Hartnett, Stephen Day, 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 (April 20, 2017): 1060–66. http://dx.doi.org/10.1177/2472555217705373.
Abstract:
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 compounds. Automation of agonist shift assays enables this data-rich analysis to evaluate a larger number of compounds, offering the potential to differentiate compound classes earlier and prospectively prioritize based on desired molecular pharmacology. A high-throughput calcium-imaging agonist shift assay was pursued to determine the allosteric parameters of over 1000 positive allosteric modulator (PAM) molecules for the human muscarinic acetylcholine receptor 1 (M1). Control compounds were run repeatedly to demonstrate internal consistency. Comparisons between potency measurements and the allosteric parameter results demonstrate that these different types of measurements do not necessarily correlate, highlighting the importance of fully characterizing and understanding the allosteric properties of leads.
34
Grundmann, Manuel, Eckhard Bender, Jens Schamberger, and Frank Eitner. "Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators." International Journal of Molecular Sciences 22, no. 4 (February 10, 2021): 1763. http://dx.doi.org/10.3390/ijms22041763.
Abstract:
The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.
35
Willard, Francis S., Ana B. Bueno, and Kyle W. Sloop. "Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor." Experimental Diabetes Research 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/709893.
Abstract:
The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.
36
Thapa, Dinesh, Elizabeth A. Cairns, Anna-Maria Szczesniak, Pushkar M. Kulkarni, Alex J. Straiker, Ganesh A. Thakur, and Melanie E. M. Kelly. "Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation." Molecules 25, no. 2 (January 20, 2020): 417. http://dx.doi.org/10.3390/molecules25020417.
Abstract:
Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury. We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia. Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2−/−) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation. Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2−/− mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation. CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.
37
Vermeulen, P. J. L., and F. G. Zitman. "Benzodiazepines in perspective (II): The GABAA-Benzodiazepine Receptor Ligands." Acta Neuropsychiatrica 12, no. 1 (March 2000): 9–18. http://dx.doi.org/10.1017/s0924270800035778.
Abstract:
SUMMARYA huge number of natural and synthetic compounds modulate the function of the γ-aminobutyric acid type A receptor (GABAA-R) by interacting with several allosteric binding sites which may differ in the various GABAA-R subtypes. The benzodiazepine receptor (BDZ-R) is the most intensively studied allosteric site. It is the first allosteric modulatory site on a neurotransmitter receptor that has been found to mediate two opposite functions: facilitation and depression of GABAA-R function. The effects of BDZ-R ligands on behavior range from agonistic (anxiolytic, anticonvulsant, myore-laxant/ataxic and hypno-sedative effects) to inverse-agonistic (anxiety and panic, hypervigilance and convulsions). Of particular interest for the future are BDZ-R partial agonists, as they lack several of the undesired properties of classic full agonists. Furthermore the GABAA-R system shows a high plasticity. This polymorphism raises the possibility that ligands selective for distinct subtypes of BDZ-R may emerge as useful drugs. In both cases the possibility exists of achieving very subtle manipulations of GABAA-R function by using allosteric modulators.
38
Vuckovic, Ziva, Patrick R. Gentry, Alice E. Berizzi, Kunio Hirata, Swapna Varghese, Geoff Thompson, Emma T. van der Westhuizen, et al. "Crystal structure of the M5muscarinic acetylcholine receptor." Proceedings of the National Academy of Sciences 116, no. 51 (November 26, 2019): 26001–7. http://dx.doi.org/10.1073/pnas.1914446116.
Abstract:
The human M5muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, a lack of structural information for this receptor subtype has limited further drug development and validation. Here we report a high-resolution crystal structure of the human M5mAChR bound to the clinically used inverse agonist, tiotropium. This structure allowed for a comparison across all 5 mAChR family members that revealed important differences in both orthosteric and allosteric sites that could inform the rational design of selective ligands. These structural studies, together with chimeric swaps between the extracellular regions of the M2and M5mAChRs, provided structural insight into kinetic selectivity, where ligands show differential residency times between related family members. Collectively, our study provides important insights into the nature of orthosteric and allosteric ligand interaction across the mAChR family that could be exploited for the design of selective drugs.
39
Jakowiecki, Jakub, Renata Abel, Urszula Orzeł, Paweł Pasznik, Robert Preissner, and Sławomir Filipek. "Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol—A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling." Molecules 26, no. 9 (April 23, 2021): 2456. http://dx.doi.org/10.3390/molecules26092456.
Abstract:
The CB1 cannabinoid receptor (CB1R) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CB1R we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach. Then, the obtained structures of CB1R with the N terminus were used for ligand docking. A natural cannabinoid receptor agonist, Δ9-THC, was docked to the orthosteric site and a negative allosteric modulator, CBD, to the allosteric site positioned between extracellular ends of helices TM1 and TM2. The molecular dynamics simulations were then performed for CB1R with ligands: (i) CBD together with THC, and (ii) THC-only. Analyses of the differences in the residue-residue interaction patterns between those two cases allowed us to elucidate the allosteric network responsible for the modulation of the CB1R by CBD. In addition, we identified the changes in the orthosteric binding mode of Δ9-THC, as well as the changes in its binding energy, caused by the CBD allosteric binding. We have also found that the presence of a complete N-terminal domain is essential for a stable binding of CBD in the allosteric site of CB1R as well as for the allosteric-orthosteric coupling mechanism.
40
Cerdan, Adrien H., Marion Sisquellas, Gilberto Pereira, Diego E. Barreto Gomes, Jean-Pierre Changeux, and Marco Cecchini. "The Glycine Receptor Allosteric Ligands Library (GRALL)." Bioinformatics 36, no. 11 (March 12, 2020): 3379–84. http://dx.doi.org/10.1093/bioinformatics/btaa170.
Abstract:
Abstract Motivation Glycine receptors (GlyRs) mediate fast inhibitory neurotransmission in the brain and have been recognized as key pharmacological targets for pain. A large number of chemically diverse compounds that are able to modulate GlyR function both positively and negatively have been reported, which provides useful information for the development of pharmacological strategies and models for the allosteric modulation of these ion channels. Results Based on existing literature, we have collected 218 unique chemical entities with documented modulatory activities at homomeric GlyR-α1 and -α3 and built a database named GRALL. This collection includes agonists, antagonists, positive and negative allosteric modulators and a number of experimentally inactive compounds. Most importantly, for a large fraction of them a structural annotation based on their putative binding site on the receptor is provided. This type of annotation, which is currently missing in other drug banks, along with the availability of cooperativity factors from radioligand displacement experiments are expected to improve the predictivity of in silico methodologies for allosteric drug discovery and boost the development of conformation-based pharmacological approaches. Availability and implementation The GRALL library is distributed as a web-accessible database at the following link: https://ifm.chimie.unistra.fr/grall. For each molecular entry, it provides information on the chemical structure, the ligand-binding site, the direction of modulation, the potency, the 3D molecular structure and quantum-mechanical charges as determined by our in-house pipeline. Contact mcecchini@unistra.fr Supplementary information Supplementary data are available at Bioinformatics online.
41
Raingeval, Claire, and Isabelle Krimm. "NMR investigation of protein–ligand interactions for G-protein coupled receptors." Future Medicinal Chemistry 11, no. 14 (July 2019): 1811–25. http://dx.doi.org/10.4155/fmc-2018-0312.
Abstract:
In this review, we report NMR studies of ligand–GPCR interactions, including both ligand-observed and protein-observed NMR experiments. Published studies exemplify how NMR can be used as a powerful tool to design novel GPCR ligands and investigate the ligand-induced conformational changes of GPCRs. The strength of NMR also lies in its capability to explore the diverse signaling pathways and probe the allosteric modulation of these highly dynamic receptors. By offering unique opportunities for the identification, structural and functional characterization of GPCR ligands, NMR will likely play a major role for the generation of novel molecules both as new tools for the understanding of the GPCR function and as therapeutic compounds for a large diversity of pathologies.
42
Nnatubeugo, Chimere, Erica Johnson, Sarah Gisondi, Felicia Roland, Werner J. Geldenhuys, Michael A. Menze, and Mary E. Konkle. "The Mitochondrial Protein MitoNEET as a Probe for the Allostery of Glutamate Dehydrogenase." Molecules 27, no. 23 (November 29, 2022): 8314. http://dx.doi.org/10.3390/molecules27238314.
Abstract:
The proteins glutamate dehydrogenase (GDH) and mitoNEET are both targets of drug development efforts to treat metabolic disorders, cancer, and neurodegenerative diseases. However, these two proteins differ starkly in the current knowledge about ligand binding sites. MitoNEET is a [2Fe-2S]-containing protein with no obvious binding site for small ligands observed in its crystal structures. In contrast, GDH is known to have a variety of ligands at multiple allosteric sites thereby leading to complex regulation in activity. In fact, while GDH can utilize either NAD(H) or NADP(H) for catalysis at the active site, only NAD(H) binds at a regulatory site to inhibit GDH activity. Previously, we found that mitoNEET forms a covalent bond with GDH in vitro and increases the catalytic activity of the enzyme. In this study we evaluated the effects of mitoNEET binding on the allosteric control of GDH conferred by inhibitors. We examined all effectors using NAD or NADP as the coenzyme to determine allosteric linkage by the NAD-binding regulatory site. We found that GDH activity, in the presence of the inhibitory palmitoyl-CoA and EGCG, can be rescued by mitoNEET, regardless of the coenzyme used. This suggests that mitoNEET rescues GDH by stabilizing the open conformation.
43
Huang, Mian, Shelby Bolin, Hannah Miller, and Ho Leung Ng. "RORγ Structural Plasticity and Druggability." International Journal of Molecular Sciences 21, no. 15 (July 27, 2020): 5329. http://dx.doi.org/10.3390/ijms21155329.
Abstract:
Retinoic acid receptor-related orphan receptor γ (RORγ) is a transcription factor regulating the expression of the pro-inflammatory cytokine IL-17 in human T helper 17 (Th17) cells. Activating RORγ can induce multiple IL-17-mediated autoimmune diseases but may also be useful for anticancer therapy. Its deep immunological functions make RORɣ an attractive drug target. Over 100 crystal structures have been published describing atomic interactions between RORɣ and agonists and inverse agonists. In this review, we focus on the role of dynamic properties and plasticity of the RORɣ orthosteric and allosteric binding sites by examining structural information from crystal structures and simulated models. We discuss the possible influences of allosteric ligands on the orthosteric binding site. We find that high structural plasticity favors the druggability of RORɣ, especially for allosteric ligands.
44
Changeux, Jean-Pierre. "The nicotinic acetylcholine receptor: a typical ‘allosteric machine’." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (May 7, 2018): 20170174. http://dx.doi.org/10.1098/rstb.2017.0174.
Abstract:
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 receptor (nAChR), links the ACh binding site to the ion channel. Pharmacological effectors, referred to as allosteric modulators, such as Ca 2+ ions and ivermectin, were discovered that enhance the transduction process when they bind to sites distinct from the orthosteric ACh site and the ion channel. The recent X-ray and electron microscopy structures, at atomic resolution, of the resting and active conformations of several homologues of the nAChR, in combination with atomistic molecular dynamics simulations reveal a stepwise quaternary transition in the transduction process with tertiary changes modifying the boundaries between subunits. These interfaces host orthosteric and allosteric modulatory sites which structural organization changes in the course of the transition. The nAChR appears as a typical allosteric machine. The model emerging from these studies has led to the conception and development of several new pharmacological agents. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.
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Schwartz, Thue W., Ulrik Gether, Hans T. Schambye, and Siv A. Hjorth. "Molecular Mechanism of Action of Non-peptide Ligands for Peptide Receptors." Current Pharmaceutical Design 1, no. 3 (October 1995): 325–42. http://dx.doi.org/10.2174/1381612801666220918163204.
Abstract:
An almost exponential development has occurred within the last five years in the area of non-peptide ligands for G protein-coupled 7TM receptors. For most of the major peptide targets a number of highly selective high affinity antagonists are today available and recently the first non-peptide agonists have started to appear as well. Mutational mapping of binding sites, which has reached a reasonably detailed level especially in the tachykinin and angiotensin systems, indicate that the peptide agonists are primarily interacting with residues located in the exterior part of the main ligand binding pocket, i.e. between the loops and the outermost segments of the trans-membrane helices. Some peptides may reach down between the helices, however, a peptide as substance P does not appear to interact at all with residues corresponding to the deeply located presumed binding site for monoamines. In contrast, presumed interaction points for non-peptide antagonists are predominantly found in the deep part of the main ligand binding pocket between the transmembrane segments. In general, it has been unexpectedly difficult and in some well characterized cases, even impossible to identify point mutations which affect both peptide agonists and non-peptide antagonists - while multiple mutations affect either one or the other ligand. These surprising observations may be explained by an allosteric receptor model where the ligands exert their effect merely by selecting and stabilizing preformed receptor conformations and thereby shifting the equilibrium towards either an active or an inactive form. In this receptor model there is no requirement for a common 'lock' for all agonists and it does not demand an overlap in binding site between competitive ligands - they can compete by binding in a mutually exclusive fashion, thus being allosteric competitive in contrast to isosteric classical competitive ligands.
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Ruiz, MariaLuisa, and Jeffrey W. Karpen. "Opening Mechanism of a Cyclic Nucleotide–gated Channel Based on Analysis of Single Channels Locked in Each Liganded State." Journal of General Physiology 113, no. 6 (June 1, 1999): 873–95. http://dx.doi.org/10.1085/jgp.113.6.873.
Abstract:
Cyclic nucleotide–gated channels contain four subunits, each with a binding site for cGMP or cAMP in the cytoplasmic COOH-terminal domain. Previous studies of the kinetic mechanism of activation have been hampered by the complication that ligands are continuously binding and unbinding at each of these sites. Thus, even at the single channel level, it has been difficult to distinguish changes in behavior that arise from a channel with a fixed number of ligands bound from those that occur upon the binding and unbinding of ligands. For example, it is often assumed that complex behaviors like multiple conductance levels and bursting occur only as a consequence of changes in the number of bound ligands. We have overcome these ambiguities by covalently tethering one ligand at a time to single rod cyclic nucleotide–gated channels (Ruiz, ML., and J.W. Karpen. 1997. Nature. 389:389–392). We find that with a fixed number of ligands locked in place the channel freely moves between three conductance states and undergoes bursting behavior. Furthermore, a thorough kinetic analysis of channels locked in doubly, triply, and fully liganded states reveals more than one kinetically distinguishable state at each conductance level. Thus, even when the channel contains a fixed number of bound ligands, it can assume at least nine distinct states. Such complex behavior is inconsistent with simple concerted or sequential allosteric models. The data at each level of liganding can be successfully described by the same connected state model (with different rate constants), suggesting that the channel undergoes the same set of conformational changes regardless of the number of bound ligands. A general allosteric model, which postulates one conformational change per subunit in both the absence and presence of ligand, comes close to providing enough kinetically distinct states. We propose an extension of this model, in which more than one conformational change per subunit can occur during the process of channel activation.
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Narlawar, Rajeshwar, J. Robert Lane, Munikumar Doddareddy, Judy Lin, Johannes Brussee, and Adriaan P. IJzerman. "Hybrid Ortho/Allosteric Ligands for the Adenosine A1Receptor." Journal of Medicinal Chemistry 53, no. 8 (April 22, 2010): 3028–37. http://dx.doi.org/10.1021/jm901252a.
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Valant, C., P. M. Sexton, and A. Christopoulos. "Orthosteric/Allosteric Bitopic Ligands: Going Hybrid at GPCRs." Molecular Interventions 9, no. 3 (June 1, 2009): 125–35. http://dx.doi.org/10.1124/mi.9.3.6.
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Selz, Karen A., Tatiana I. Samoylova, Alexandre M. Samoylov, Vitaly J. Vodyanoy, and Arnold J. Mandell. "Designing allosteric peptide ligands targeting a globular protein." Biopolymers 85, no. 1 (2006): 38–59. http://dx.doi.org/10.1002/bip.20607.
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Radchenko, E. V., A. S. Tarakanova, D. S. Karlov, M. I. Lavrov, and V. A. Palyulin. "Ligands of the AMPA-subtype glutamate receptors: mechanisms of action and novel chemotypes." Biomeditsinskaya Khimiya 67, no. 3 (2021): 187–200. http://dx.doi.org/10.18097/pbmc20216703187.
Abstract:
Ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype play a key role in synaptic plasticity representing one of the mechanisms for learning and memory formation. They can also serve as targets for the development of novel classes of pharmaceuticals for the treatment or substantive correction of many serious neurodegenerative and psychoneurological disorders. The search and studies of various types of AMPA receptor ligands attract considerable attention from academic organizations and pharmaceutical companies all over the world. This review mainly focuses on recent advances in this field. The architecture and operational mechanism of the receptor as well as its major binding sites and ligand types are considered. Special attention is paid to the studies of mechanisms of action and novel chemotypes of AMPA receptor agonists and competitive antagonists, positive and negative allosteric modulators, auxiliary protein-dependent allosteric modulators, and ion channel blockers.