scholarly journals Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1613
Author(s):  
Giulia D’Arrigo ◽  
Eleonora Gianquinto ◽  
Giulia Rossetti ◽  
Gabriele Cruciani ◽  
Stefano Lorenzetti ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Fruits And Vegetables ◽  
Computational Prediction ◽  
Membrane Receptors ◽  
Computational Docking ◽  
Docking Simulations ◽  
Mediated Effects ◽  
17Β Estradiol ◽  
G Protein Coupled ◽  
Relevant Degree

Flavonoids are plant bioactives that are recognized as hormone-like polyphenols because of their similarity to the endogenous sex steroids 17β-estradiol and testosterone, and to their estrogen- and androgen-like activity. Most efforts to verify flavonoid binding to nuclear receptors (NRs) and explain their action have been focused on ERα, while less attention has been paid to other nuclear and non-nuclear membrane androgen and estrogen receptors. Here, we investigate six flavonoids (apigenin, genistein, luteolin, naringenin, quercetin, and resveratrol) that are widely present in fruits and vegetables, and often used as replacement therapy in menopause. We performed comparative computational docking simulations to predict their capability of binding nuclear receptors ERα, ERβ, ERRβ, ERRγ, androgen receptor (AR), and its variant ART877A and membrane receptors for androgens, i.e., ZIP9, GPRC6A, OXER1, TRPM8, and estrogens, i.e., G Protein-Coupled Estrogen Receptor (GPER). In agreement with data reported in literature, our results suggest that these flavonoids show a relevant degree of complementarity with both estrogen and androgen NR binding sites, likely triggering genomic-mediated effects. It is noteworthy that reliable protein–ligand complexes and estimated interaction energies were also obtained for some suggested estrogen and androgen membrane receptors, indicating that flavonoids could also exert non-genomic actions. Further investigations are needed to clarify flavonoid multiple genomic and non-genomic effects. Caution in their administration could be necessary, until the safe assumption of these natural molecules that are largely present in food is assured.

Covalent-Fragment Screening of Brd4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites

2019 ◽  
Author(s):  
Michael Olp ◽  
Daniel Sprague ◽  
Stefan Kathman ◽  
Ziyang Xu ◽  
Alexandar Statsyuk ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Binding Site ◽  
Binding Sites ◽  
Computational Prediction ◽  
Chemical Probes ◽  
Computational Docking ◽  
Fragment Screening ◽  
Covalent Inhibitors ◽  
Bet Protein ◽  
Proof Of Principle

<p>Brd4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin. Alternative chemical probes that act orthogonally to the highly-conserved acetyl-lysine binding sites may exhibit selectivity within the BET family and avoid recently reported toxicity in clinical trials of BET bromodomain inhibitors. Here, we report the first identification of a ligandable site on a bromodomain outside the acetyl-lysine binding site. Inspired by our computational prediction of hotspots adjacent to non-homologous cysteine residues within the <i>C</i>-terminal Brd4 bromodomain (Brd4-BD2), we performed a mid-throughput mass spectrometry screen to identify cysteine-reactive fragments that covalently and selectively modify Brd4. Subsequent mass spectrometry, NMR and computational docking analyses of electrophilic fragment hits revealed a novel ligandable site near Cys356 that is unique to Brd4 among all human bromodomains. This site is orthogonal to the Brd4-BD2 acetyl-lysine binding site as Cys356 modification did not impact binding of the pan-BET bromodomain inhibitor JQ1 in fluorescence polarization assays. Finally, we tethered covalent fragments to JQ1 and performed NanoBRET assays to provide proof of principle that this orthogonal site can be covalently targeted in intact human cells. Overall, we demonstrate the potential of targeting sites orthogonal to bromodomain acetyl-lysine binding sites to develop bivalent and covalent inhibitors that displace Brd4 from chromatin.</p>

Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors

2019 ◽  
Vol 25 (26) ◽  
pp. 2892-2905 ◽  
Author(s):  
Sumit Jamwal ◽  
Ashish Mittal ◽  
Puneet Kumar ◽  
Dana M. Alhayani ◽  
Amal Al-Aboudi
Keyword(s):  
Nervous System ◽  
Therapeutic Potential ◽  
The Body ◽  
Membrane Receptors ◽  
Physiological Importance ◽  
Physiological Processes ◽  
Central Nervous Systems ◽  
Energy Consuming ◽  
Metabolic Dysfunctions ◽  
G Protein Coupled

Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.

A Review on Melatonin’s Effects in Cancer: Potential Mechanisms

2018 ◽  
Vol 18 (7) ◽  
pp. 985-992 ◽  
Author(s):  
Aysegul Hanikoglu ◽  
Ertan Kucuksayan ◽  
Rana Cagla Akduman ◽  
Tomris Ozben
Keyword(s):  
Systematic Review ◽  
Antioxidant Activity ◽  
Membrane Receptors ◽  
Cancer Development ◽  
Secretory Product ◽  
Prevention And Treatment ◽  
G Protein Coupled

This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.

scholarly journals Human Homologs of the Putative G Protein-Coupled Membrane Progestin Receptors (mPRα, β, and γ) Localize to the Endoplasmic Reticulum and Are Not Activated by Progesterone

2006 ◽  
Vol 20 (12) ◽  
pp. 3146-3164 ◽  
Author(s):  
Tom Krietsch ◽  
Maria Sofia Fernandes ◽  
Jukka Kero ◽  
Ralf Lösel ◽  
Maria Heyens ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
G Protein ◽  
Cell Lines ◽  
Spotted Seatrout ◽  
Membrane Receptors ◽  
Takifugu Rubripes ◽  
Camp Production ◽  
Intact Cells ◽  
Progestin Receptors ◽  
G Protein Coupled

Abstract The steroid hormone progesterone exerts pleiotrophic functions in many cell types. Although progesterone controls transcriptional activation through binding to its nuclear receptors, it also initiates rapid nongenomic signaling events. Recently, three putative membrane progestin receptors (mPRα, β, and γ) with structural similarity to G protein-coupled receptors have been identified. These mPR isoforms are expressed in a tissue-specific manner and belong to the larger, highly conserved family of progestin and adiponectin receptors found in plants, eubacteria, and eukaryotes. The fish mPRα has been reported to mediate progesterone-dependent MAPK activation and inhibition of cAMP production through coupling to an inhibitory G protein. To functionally characterize the human homologs, we established human embryonic kidney 293 and MDA-MB-231 cell lines that stably express human mPRα, β, or γ. For comparison, we also established cell lines expressing the mPRα cloned from the spotted seatrout (Cynoscion nebulosus) and Japanese pufferfish (Takifugu rubripes). Surprisingly, we found no evidence that human or fish mPRs regulate cAMP production or MAPK (ERK1/2 or p38) activation upon progesterone stimulation. Furthermore, the mPRs did not couple to a highly promiscuous G protein subunit, Gαq5i, in transfection studies or provoke Ca2+ mobilization in response to progesterone. Finally, we demonstrate that transfected mPRs, as well as endogenous human mPRα, localize to the endoplasmic reticulum, and that their expression does not lead to increased progestin binding either in membrane preparations or in intact cells. Our results therefore do not support the concept that mPRs are plasma membrane receptors involved in transducing nongenomic progesterone actions.

scholarly journals Molecular Dynamics Scoring of Protein–Peptide Models Derived from Coarse-Grained Docking

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3293
Author(s):  
Mateusz Zalewski ◽  
Sebastian Kmiecik ◽  
Michał Koliński
Keyword(s):  
Molecular Dynamics ◽  
Geometry Optimization ◽  
Computational Prediction ◽  
Md Simulations ◽  
Coarse Grained ◽  
Ligand Interaction ◽  
Vast Number ◽  
Docking Simulations ◽  
Peptide Models ◽  
Peptide Complexes

One of the major challenges in the computational prediction of protein–peptide complexes is the scoring of predicted models. Usually, it is very difficult to find the most accurate solutions out of the vast number of sometimes very different and potentially plausible predictions. In this work, we tested the protocol for Molecular Dynamics (MD)-based scoring of protein–peptide complex models obtained from coarse-grained (CG) docking simulations. In the first step of the scoring procedure, all models generated by CABS-dock were reconstructed starting from their original C-alpha trace representations to all-atom (AA) structures. The second step included geometry optimization of the reconstructed complexes followed by model scoring based on receptor–ligand interaction energy estimated from short MD simulations in explicit water. We used two well-known AA MD force fields, CHARMM and AMBER, and a CG MARTINI force field. Scoring results for 66 different protein–peptide complexes show that the proposed MD-based scoring approach can be used to identify protein–peptide models of high accuracy. The results also indicate that the scoring accuracy may be significantly affected by the quality of the reconstructed protein receptor structures.

scholarly journals The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1

2016 ◽  
Vol 41 (12) ◽  
pp. 1303-1310 ◽  
Author(s):  
Guan-Yu Ren ◽  
Chun-Yang Chen ◽  
Wei-Guo Chen ◽  
Ya Huang ◽  
Li-Qiang Qin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Estrogen Receptor ◽  
Benign Prostatic Hyperplasia ◽  
G Protein ◽  
Therapeutic Potential ◽  
Prostatic Hyperplasia ◽  
Docking Simulations ◽  
G Protein Coupled

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.

scholarly journals Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

2010 ◽  
Vol 45 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Davide Calebiro ◽  
Viacheslav O Nikolaev ◽  
Martin J Lohse
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
Current Model ◽  
Living Cells ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Optical Methods ◽  
Camp Signaling ◽  
Gpcr Signaling ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

Inhibition of tyrosinase by fumaric acid: Integration of inhibition kinetics with computational docking simulations

2017 ◽  
Vol 105 ◽  
pp. 1663-1669 ◽  
Author(s):  
Lin Gou ◽  
Jinhyuk Lee ◽  
Jun-Mo Yang ◽  
Yong-Doo Park ◽  
Hai-Meng Zhou ◽  
...  
Keyword(s):  
Fumaric Acid ◽  
Inhibition Kinetics ◽  
Computational Docking ◽  
Docking Simulations

A generic microfluidic biosensor of G protein-coupled receptor activation – impedance measurements of reversible morphological changes of reverse transfected HEK293 cells on microelectrodes

RSC Advances ◽  
2015 ◽  
Vol 5 (65) ◽  
pp. 52563-52570 ◽  
Author(s):  
Saurabh K. Srivastava ◽  
Rajesh Ramaneti ◽  
Margriet Roelse ◽  
Hien Duy Tong ◽  
Elwin X. Vrouwe ◽  
...  
Keyword(s):  
G Protein ◽  
Morphological Changes ◽  
Receptor Activation ◽  
Membrane Receptors ◽  
Hek293 Cells ◽  
G Protein Coupled Receptor ◽  
Impedance Measurements ◽  
Transfected Cells ◽  
Microfluidic Biosensor ◽  
G Protein Coupled

Flowcell with micro-IDEs (250–500 μm) covered with both stable and reverse transfected cells overexpressing membrane receptors to demonstrate impedance responses to serial injections of analyte.

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