共查询到20条相似文献,搜索用时 15 毫秒
1.
Niels J. Hauwert Tamara A. M. Mocking Daniel DaCostaPereira Ken Lion Yara Huppelschoten Henry F. Vischer Iwan J. P. DeEsch Maikel Wijtmans Rob Leurs 《Angewandte Chemie (International ed. in English)》2019,58(14):4531-4535
Spatiotemporal control over biochemical signaling processes involving G protein‐coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H3 receptor (hH3R). Upon illumination, key compound 65 decreases its affinity for the hH3R by 8.5‐fold and its potency in hH3R‐mediated Gi protein activation by over 20‐fold, with the trans and cis isomer both acting as full agonist. In real‐time two‐electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light‐induced modulation of hH3R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation. 相似文献
2.
Dr. David Wifling Dr. Christopher Pfleger Jonas Kaindl Passainte Ibrahim Dr. Ralf C. Kling Prof. Dr. Armin Buschauer Prof. Dr. Holger Gohlke Prof. Dr. Timothy Clark 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(64):14613-14624
Histamine H4 receptor (H4R) orthologues are G-protein-coupled receptors (GPCRs) that exhibit species-dependent basal activity. In contrast to the basally inactive mouse H4R (mH4R), human H4R (hH4R) shows a high degree of basal activity. We have performed long-timescale molecular dynamics simulations and rigidity analyses on wild-type hH4R, the experimentally characterized hH4R variants S179M, F169V, F169V+S179M, F168A, and on mH4R to investigate the molecular nature of the differential basal activity. H4R variant-dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F16945.55 dips into the orthosteric binding pocket only in the case of hH4R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H4R activation that are of importance for other GPCRs. 相似文献
3.
Kamil J. Kuder Magdalena Kotaska Katarzyna Szczepaska Kamil Mika David Reiner-Link Holger Stark Katarzyna Kie-Kononowicz 《Molecules (Basel, Switzerland)》2021,26(8)
In an attempt to find new dual acting histamine H3 receptor (H3R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H3 receptor (hH3R) ligand KSK63. As a result, 15 obtained compounds show moderate hH3R affinity, the best being the compound 17 (hH3R Ki = 518 nM). Docking to the histamine H3R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound 16 (hH3R Ki = 592 nM) showed the strongest antioxidant properties at the concentration of 10−4 mol/L. It significantly reduced the amount of free radicals presenting 50–60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH3R affinity, 16 (QD13) constitutes a starting point for the search of potential dual acting H3R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress. 相似文献
4.
Functional Dynamics of Deuterated β2‐Adrenergic Receptor in Lipid Bilayers Revealed by NMR Spectroscopy 下载免费PDF全文
Dr. Yutaka Kofuku Dr. Takumi Ueda Junya Okude Yutaro Shiraishi Keita Kondo Takuya Mizumura Shiho Suzuki Prof. Dr. Ichio Shimada 《Angewandte Chemie (International ed. in English)》2014,53(49):13376-13379
G‐protein‐coupled receptors (GPCRs) exist in conformational equilibrium between active and inactive states, and the former population determines the efficacy of signaling. However, the conformational equilibrium of GPCRs in lipid bilayers is unknown owing to the low sensitivities of their NMR signals. To increase the signal intensities, a deuteration method was developed for GPCRs expressed in an insect cell/baculovirus expression system. The NMR sensitivities of the methionine methyl resonances from the β2‐adrenergic receptor (β2AR) in lipid bilayers of reconstituted high‐density lipoprotein (rHDL) increased by approximately 5‐fold upon deuteration. NMR analyses revealed that the exchange rates for the conformational equilibrium of β2AR in rHDLs were remarkably different from those measured in detergents. The timescales of GPCR signaling, calculated from the exchange rates, are faster than those of receptor tyrosine kinases and thus enable rapid neurotransmission and sensory perception. 相似文献
5.
Dr. Shuguang Yuan Dr. H. C. Stephen Chan Prof. Horst Vogel Prof. Slawomir Filipek Prof. Raymond C. Stevens Prof. Krzysztof Palczewski 《Angewandte Chemie (International ed. in English)》2016,55(35):10331-10335
Human purinergic G protein‐coupled receptor P2Y1 (P2Y1R) is activated by adenosine 5′‐diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all‐atom long‐timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1R activation. 相似文献
6.
Photoswitching the Efficacy of a Small‐Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism 下载免费PDF全文
Prashanna Vijayachandran Daniel Da Costa Pereira Jan Paul M. Bebelman Prof. Dr. Iwan J. P. de Esch Dr. Henry F. Vischer Dr. Maikel Wijtmans Prof. Dr. Rob Leurs 《Angewandte Chemie (International ed. in English)》2018,57(36):11608-11612
For optical control of GPCR function, we set out to develop small‐molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects, that is, stimulate or antagonize GPCR activation. Our design was based on a previously identified efficacy hotspot for the peptidergic chemokine receptor CXCR3 and resulted in the synthesis and characterization of five new azobenzene‐containing CXCR3 ligands. G protein activation assays and real‐time electrophysiology experiments demonstrated photoswitching from antagonism to partial agonism and even to full agonism (compound VUF16216). SAR evaluation suggests that the size and electron‐donating properties of the substituents on the inner aromatic ring are important for the efficacy photoswitching. These compounds are the first GPCR azo ligands with a nearly full efficacy photoswitch and may become valuable pharmacological tools for the optical control of peptidergic GPCR signaling. 相似文献
7.
Johannes Broichhagen Tom Podewin Helena Meyer‐Berg Yorrick vonOhlen Natalie R. Johnston Ben J. Jones Stephen R. Bloom Guy A. Rutter Anja Hoffmann‐Rder David J. Hodson Dirk Trauner 《Angewandte Chemie (International ed. in English)》2015,54(51):15565-15569
Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off‐target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon‐like peptide‐1 receptor (GLP‐1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo , possesses an azobenzene photoresponsive element, affording isomer‐biased GLP‐1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival. 相似文献
8.
Noureldin Saleh Dr. Giorgio Saladino Prof. Dr. Francesco L. Gervasio Elke Haensele Dr. Lee Banting Dr. David C. Whitley Prof. Dr. Jana Sopkova‐de Oliveira Santos Prof. Ronan Bureau Prof. Dr. Timothy Clark 《Angewandte Chemie (International ed. in English)》2016,55(28):8008-8012
Molecular‐dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V2‐receptor (V2R). Two of these, the vestibule and intermediate sites, block (antagonize) the receptor, and the third is the orthosteric activation (agonist) site. The contacts found for the orthosteric site satisfy all the requirements deduced from mutagenesis experiments. Metadynamics simulations for V2R and its V1aR‐analog give an excellent correlation with experimental binding free energies by assuming that the most stable binding site in the simulations corresponds to the experimental binding free energy in each case. The resulting three‐site mechanism separates agonists from antagonists and explains subtype selectivity. 相似文献
9.
Dr. Steffen Pockes Dr. David Wifling Prof. Dr. Armin Buschauer Prof. Dr. Sigurd Elz 《ChemistryOpen》2019,8(3):285-297
New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 ( 2 ). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S-methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies. 相似文献
10.
Dr. Johannes Broichhagen Natalie R. Johnston Yorrick von Ohlen Helena Meyer‐Berg Dr. Ben J. Jones Prof. Dr. Stephen R. Bloom Prof. Dr. Guy A. Rutter Prof. Dr. Dirk Trauner Dr. David J. Hodson 《Angewandte Chemie (International ed. in English)》2016,55(19):5865-5868
Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G‐protein‐coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light‐activated positive allosteric modulator of the glucagon‐like peptide‐1 receptor (GLP‐1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca2+, cAMP, and insulin responses to glucagon‐like peptide‐1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small‐molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP‐1R. 相似文献
11.
Dr. Els Pardon Dr. Cecilia Betti Dr. Toon Laeremans Dr. Florent Chevillard Dr. Karel Guillemyn Prof. Dr. Peter Kolb Prof. Dr. Steven Ballet Prof. Dr. Jan Steyaert 《Angewandte Chemie (International ed. in English)》2018,57(19):5292-5295
The conformational complexity of transmembrane signaling of G‐protein‐coupled receptors (GPCRs) is a central hurdle for the design of screens for receptor agonists. In their basal states, GPCRs have lower affinities for agonists compared to their G‐protein‐bound active state conformations. Moreover, different agonists can stabilize distinct active receptor conformations and do not uniformly activate all cellular signaling pathways linked to a given receptor (agonist bias). Comparative fragment screens were performed on a β2‐adrenoreceptor–nanobody fusion locked in its active‐state conformation by a G‐protein‐mimicking nanobody, and the same receptor in its basal‐state conformation. This simple biophysical assay allowed the identification and ranking of multiple novel agonists and permitted classification of the efficacy of each hit in agonist, antagonist, or inverse agonist categories, thereby opening doors to nanobody‐enabled reverse pharmacology. 相似文献
12.
Andrew Coop Ilona Berzetei‐Gurske Jackie Burnside Lawrence Toll JohnR. Traynor StephenM. Husbands JohnW. Lewis 《Helvetica chimica acta》2000,83(4):687-693
A series of ethers of 7,8‐cyclopenta‐fused analogs of the orvinols related to buprenorphine were prepared and evaluated in opioid‐binding and functional assays. Comparison of the ethyl ethers 4b and 5b with the parent alcohols 4a and 5a , respectively, in both the (5′R) (=5′β) and (5′S) (=5′α) series, shows that the 20‐OH group in the orvinols (corresponding to 5′‐OH of 4 and 5 ) is not crucial for opioid activity, although in the [35S]GTPγS assay, the 5′β‐ethyl ether 4b had 80‐fold greater κ‐agonist potency than its epimer 5b . Increasing the size of the 5′β‐OR group has a major effect on μ‐agonist efficacy and potency, a more modest effect on δ‐efficacy, and no effect on κ‐activity. These data show that μ‐ and δ‐agonist efficacy is favoured by lipophilic binding in the area occupied by the tBu in the lowest‐energy conformation of buprenorphine, and that κ‐agonist binding may involve interaction with an H‐bond‐donor group in that region. 相似文献
13.
Poh Wai Chia Dr. Matthew R. Livesey Prof. Dr. Alexandra M. Z. Slawin Dr. Tanja van Mourik Prof. Dr. David J. A. Wyllie Prof. Dr. David O'Hagan 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(28):8813-8819
N‐Methyl‐D ‐aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C? F bond at the 3‐position of (S)‐NMDA generates either the (2S,3S)‐ or (2S,3R)‐ diastereoisomers of 3F‐NMDA. The individual diastereoisomers were prepared by synthesis in enantiomerically pure forms and it was found that (2S,3S)‐3F‐NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)‐diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C? F bond (2S,3S)‐3F‐NMDA to adopt a gauche conformation to the C? N+ bond in the binding conformation, whereas the (2S,3R)‐3F‐NMDA forces these bonds anti, losing electrostatic stabilisation, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the molecular conformation of β‐fluorinated amino acids and thus probing the active conformations of bioactive compounds at receptors. 相似文献
14.
Luca Agnetta Michael Kauk Maria Consuelo Alonso Canizal Regina Messerer Prof. Dr. Ulrike Holzgrabe Prof. Dr. Carsten Hoffmann Prof. Dr. Michael Decker 《Angewandte Chemie (International ed. in English)》2017,56(25):7282-7287
The investigation of the mode and time course of the activation of G-protein-coupled receptors (GPCRs), in particular muscarinic acetylcholine (mACh or M) receptors, is still in its infancy despite the tremendous therapeutic relevance of M receptors and GPCRs in general. We herein made use of a dualsteric ligand that can concomitantly interact with the orthosteric, that is, the neurotransmitter, binding site and an allosteric one. We synthetically incorporated a photoswitchable (photochromic) azobenzene moiety. We characterized the photophysical properties of this ligand called BQCAAI and investigated its applicability as a pharmacological tool compound with a set of FRET techniques at the M1 receptor. BQCAAI proved to be an unprecedented molecular tool; it is the first photoswitchable dualsteric ligand, and its activity can be regulated by light. We also applied BQCCAI to investigate the time course of several receptor activation processes. 相似文献
15.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(38):11707-11711
We describe two water‐soluble ruthenium complexes, [ 1 ]Cl2 and [ 2 ]Cl2, that photodissociate to release a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with a low dose (21 J cm−2) of red light in an oxygen‐independent manner. Using a specific NAMPT activity assay, up to an 18‐fold increase in inhibition potency was measured upon red‐light activation of [ 2 ]Cl2, while [ 1 ]Cl2 was thermally unstable. For the first time, the dark and red‐light‐induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1 % O2). In skin (A431) and lung (A549) cancer cells, a 3‐ to 4‐fold increase in cytotoxicity was found upon red‐light irradiation for [ 2 ]Cl2, whether the cells were cultured and irradiated with 1 % or 21 % O2. These results demonstrate the potential of photoactivated chemotherapy for hypoxic cancer cells, in which classical photodynamic therapy, which relies on oxygen activation, is poorly efficient. 相似文献
16.
Sirish Kaushik Lakkaraju Justin A. Lemkul Jing Huang Alexander D. MacKerell Jr. 《Journal of computational chemistry》2016,37(4):416-425
The conformational dynamics of a macromolecule can be modulated by a number of factors, including changes in environment, ligand binding, and interactions with other macromolecules, among others. We present a method that quantifies the differences in macromolecular conformational dynamics and automatically extracts the structural features responsible for these changes. Given a set of molecular dynamics (MD) simulations of a macromolecule, the norms of the differences in covariance matrices are calculated for each pair of trajectories. A matrix of these norms thus quantifies the differences in conformational dynamics across the set of simulations. For each pair of trajectories, covariance difference matrices are parsed to extract structural elements that undergo changes in conformational properties. As a demonstration of its applicability to biomacromolecular systems, the method, referred to as DIRECT‐ID, was used to identify relevant ligand‐modulated structural variations in the β2‐adrenergic (β2AR) G‐protein coupled receptor. Micro‐second MD simulations of the β2AR in an explicit lipid bilayer were run in the apo state and complexed with the ligands: BI‐167107 (agonist), epinephrine (agonist), salbutamol (long‐acting partial agonist), or carazolol (inverse agonist). Each ligand modulated the conformational dynamics of β2AR differently and DIRECT‐ID analysis of the inverse‐agonist vs. agonist‐modulated β2AR identified residues known through previous studies to selectively propagate deactivation/activation information, along with some previously unidentified ligand‐specific microswitches across the GPCR. This study demonstrates the utility of DIRECT‐ID to rapidly extract functionally relevant conformational dynamics information from extended MD simulations of large and complex macromolecular systems. © 2015 Wiley Periodicals, Inc. 相似文献
17.
Ian Derrick StephenM. Husbands Jillian Broadbear JohnR. Traynor JamesH. Woods JohnW. Lewis 《Helvetica chimica acta》2000,83(12):3122-3130
Methods have been developed for the synthesis of 7α‐amino‐ and 7α‐(aminomethyl)‐N‐cyclopropylmethyl‐6,14‐endo‐ethanotetrahydronororipavines and their cinnamoyl derivatives (Schemes 1 and 3). In displacement binding assays, the cinnamoyl derivatives 4c and 5c had high affinity for opioid receptors, but no particular selectivity for any receptor type or differences in affinity between 4c and 5c (Table 1). In tissue assays for opioid receptor function, in which both 4c and 5c were potent antagonists, the aminomethyl derivative 5c was 20‐ to 70‐fold more potent than the amino derivative 4c (Table 2). These data are in keeping with previously reported in vivo data and confirm the major effect of the methylene spacer in 5c . 相似文献
18.
Distinct Spatial Relationship of the Interleukin‐9 Receptor with Interleukin‐2 Receptor and Major Histocompatibility Complex Glycoproteins in Human T Lymphoma Cells 下载免费PDF全文
Enikő Nizsalóczki István Csomós Dr. Péter Nagy Dr. Zsolt Fazekas Dr. Carolyn K. Goldman Dr. Thomas A. Waldmann Dr. Sándor Damjanovich Dr. György Vámosi Dr. László Mátyus Dr. Andrea Bodnár 《Chemphyschem》2014,15(18):3969-3978
19.
Dr. N. Kodiah Beyeh Dr. Fangfang Pan Dr. Sandip Bhowmik Toni Mäkelä Prof. Robin H. A. Ras Acad. Prof. Kari Rissanen 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(4):1355-1361
N‐Alkyl ammonium resorcinarene salts (NARYs, Y=triflate, picrate, nitrate, trifluoroacetates and NARBr) as tetravalent receptors, are shown to have a strong affinity for chlorides. The high affinity for chlorides was confirmed from a multitude of exchange experiments in solution (NMR and UV/Vis), gas phase (mass spectrometry), and solid‐state (X‐ray crystallography). A new tetra‐iodide resorcinarene salt (NARI) was isolated and fully characterized from exchange experiments in the solid‐state. Competition experiments with a known monovalent bis‐urea receptor ( 5 ) with strong affinity for chloride, reveals these receptors to have a much higher affinity for the first two chlorides, a similar affinity as 5 for the third chloride, and lower affinity for the fourth chloride. The receptors affinity toward chloride follows the trend K1?K2?K3≈ 5 >K4, with Ka=5011 m ?1 for 5 in 9:1 CDCl3/[D6]DMSO. 相似文献
20.
r‐1, c‐2, t‐3, t‐4‐1,3‐Bis[2‐(5‐R‐benzoxazolyl)]‐2,4‐di(4‐R'‐phenyl)cyclobutane (IIa: R=R' = H; IIb: R=Me, R'= H; IIc: R = Me, R' = OMe) was synthesized with high stereo‐selectivity by the photodimerization of trans‐l‐[2‐(5‐R‐benzoxazolyl)]‐2‐(4‐R'‐phenyl) ethene (Ia: R=R' = H; Ib: R = Me, R' = H; Ic: R = Me, R' = OMe) in sulfuric acid. The structures of IIa–IIc were identified by elemental analysis, IR, UV, 1H NMR, 13C NMR and MS. The molecular and crystal structure of IIc has been determined by X‐ray diffraction method. The crystal of IIc (C34H30N2O4. 0.5C2OH) is monoclinic, space group P21/n with cell dimensions of a = 1.5416(3), b =0.5625(1), c = 1.7875(4) nm, β = 91.56 (3)°, V= 1.550(1) nm3, Z = 2. The structure shows that the molecule of IIc is centrosymmetric, which indicates that the dimerization process is a head‐to‐tail fashion. The selectivity of the photodimerization of Ia–Ic has been enhanced by using acidic solvent and the reaction speed would be decreased when electron donating group was introduced in the 4‐position of the phenyl group. That the photodimerization is not affected by the presence of oxygen as well as its high stereo‐selectivity demonstrated that the reaction proceeded through an excited singlet state. It was also found that under irradiation of short wavelength UV, these dimers underwent photolysis completely to reproduce its trans‐monomers, and then the new formed species changed into their cis‐isomers through trans‐cis isomerization. 相似文献