@article{MTMT:30750987,
	title = {Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors},
	url = {https://m2.mtmt.hu/api/publication/30750987},
	author = {Dvorácskó, Szabolcs and Keresztes, Attila and Mollica, A. and Stefanucci, A. and Macedonio, G. and Pieretti, S. and Zádor, Ferenc and Walter, Fruzsina and Deli, Mária Anna and Kékesi, Gabriella and Bánki, László and Tuboly, Gábor and Horváth, Gyöngyi and Tömböly, Csaba},
	doi = {10.1016/j.ejmech.2019.05.037},
	journal-iso = {EUR J MED CHEM},
	journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY},
	volume = {178},
	unique-id = {30750987},
	issn = {0223-5234},
	abstract = {In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 μg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties. © 2019 Elsevier Masson SAS},
	keywords = {ANTINOCICEPTION; ARTICLE; controlled study; nonhuman; animal model; animal experiment; animal cell; in vitro study; DRUG DESIGN; unclassified drug; binding affinity; Drug targeting; in vivo study; chronic pain; RADIOLIGAND; drug receptor binding; ligand binding; analgesic activity; mu opiate receptor; rimonabant; drug binding site; cannabinoid receptor; antinociceptive agent; oxycodone; cannabinoid receptor agonist; cannabinoid receptor agonist; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine; brain membrane; hot plate test; inhibition constant; mu opiate receptor agonist; Multi-targeting; rat; Bivalent ligand; Mu opioid receptor agonist; PIGFJYFWBSMSFM-WKSKUSBCSA-N; 3 (1 naphthoyl) 1 pentylindole; 6 [3 (1 n aphthoyl) 1h indol 1 yl]hexanoic acid; n [5 [3 (1 naphthoyl) 1h indol 1 yl]pentyl]acetamide; naphthalen 1 yl(5 bromo 1 pentyl 1h indol 3 yl)methanone; oxycodone o carboxymethyloxime; oxycodone o [n (13 amino 4,7,10 trioxatridecyl)carboxamidomethyl]oxime; oxycodone o [n (2 aminoethyl)carboxamidomethyl]oxime; oxycodone o [n(6 aminohexyl)carboxamidomethyl]oxime; tyrosyl dextro alanylglycylphenylalaninamide; [1 (5 aminopentyl) 1h indol 3 yl](naphthalen 1 yl)methanone},
	year = {2019},
	eissn = {1768-3254},
	pages = {571-588},
	orcid-numbers = {Walter, Fruzsina/0000-0001-8145-2823; Deli, Mária Anna/0000-0001-6084-6524; Kékesi, Gabriella/0000-0002-0185-2155; Horváth, Gyöngyi/0000-0002-6025-4577}
}

@article{MTMT:3315334,
	title = {The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases},
	url = {https://m2.mtmt.hu/api/publication/3315334},
	author = {Penke, Botond and Fülöp, Lívia and Szűcs, Mária and Frecska, Ede},
	doi = {10.2174/1570159X15666170529104323},
	journal-iso = {CURR NEUROPHARMACOL},
	journal = {CURRENT NEUROPHARMACOLOGY},
	volume = {16},
	unique-id = {3315334},
	issn = {1570-159X},
	abstract = {Background: Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. Methods: Research articles on Sigma-1 receptor were reviewed. Results: ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. Conclusion: Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity.},
	keywords = {ANTAGONIST; RAT-BRAIN; ALZHEIMERS-DISEASE; IN-VITRO; PHARMACOLOGY; AGONIST; LIGAND-BINDING; HIGH-AFFINITY BINDING; ENDOPLASMIC-RETICULUM; neurodegenerative diseases; chaperone; TRAUMATIC BRAIN-INJURY; AMYOTROPHIC-LATERAL-SCLEROSIS; Unfolded protein response; Sigma-1 receptor; STEROL C-8-C-7 ISOMERASE; DMT},
	year = {2018},
	eissn = {1875-6190},
	pages = {97-116},
	orcid-numbers = {Penke, Botond/0000-0003-0938-0567; Fülöp, Lívia/0000-0002-8010-0129}
}

@article{MTMT:2470032,
	title = {The Impact of Molecular Dynamics Sampling on the Performance of Virtual Screening against GPCRs},
	url = {https://m2.mtmt.hu/api/publication/2470032},
	author = {Tarcsay, Ákos and Paragi, Gábor and Vass, Márton and Jójárt, Balázs and Bogár, Ferenc and Keserű, György Miklós},
	doi = {10.1021/ci400087b},
	journal-iso = {J CHEM INF MODEL},
	journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING},
	volume = {53},
	unique-id = {2470032},
	issn = {1549-9596},
	abstract = {The formation of ligand?protein complexes requires simultaneous adaptation of the binding partners. In structure based virtual screening, high throughput docking approaches typically consider the ligand flexibility, but the conformational freedom of the protein is usually taken into account in a limited way. The goal of this study is to elaborate a methodology for incorporating protein flexibility to improve the virtual screening enrichments on GPCRs. Explicit-solvated molecular dynamics simulations (MD) were carried out in lipid bilayers to generate an ensemble of protein conformations for the X-ray structures and homology models of both aminergic and peptidergic GPCRs including the chemokine CXCR4, dopamine D3, histamine H4, and serotonin 5HT6 holo receptor complexes. The quality of the receptor models was assessed by enrichment studies to compare X-ray structures, homology models, and snapshots from the MD trajectory. According to our results, selected frames from the MD trajectory can outperform X-ray structures and homology models in terms of enrichment factor and AUC values. Significant changes were observed considering EF1% values: comparing the original CXCR4, D3, and H4 targets and the additional 5HT6 initial models to that of the best MD frame resulted in 0 to 6.7, 0.32 to 3.5 (10?), 13.3 to 26.7 (2?), and 0 to 14.1 improvements, respectively. It is worth noting that rank-average based ensemble evaluation calculated for different ensemble sizes could not improve the results further. We propose here that MD simulation can capture protein conformations representing the key interacting points of the receptor but less biased toward one specific chemotype. These conformations are useful for the identification of a ?consensus? binding site with improved performance in virtual screening.},
	year = {2013},
	eissn = {1549-960X},
	pages = {2990-2999},
	orcid-numbers = {Paragi, Gábor/0000-0001-5408-1748; Bogár, Ferenc/0000-0002-0611-1452}
}