TY - JOUR AU - Dvorácskó, Szabolcs AU - Keresztes, Attila AU - Mollica, A. AU - Stefanucci, A. AU - Macedonio, G. AU - Pieretti, S. AU - Zádor, Ferenc AU - Walter, Fruzsina AU - Deli, Mária Anna AU - Kékesi, Gabriella AU - Bánki, László AU - Tuboly, Gábor AU - Horváth, Gyöngyi AU - Tömböly, Csaba TI - Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 178 PY - 2019 SP - 571 EP - 588 PG - 18 SN - 0223-5234 DO - 10.1016/j.ejmech.2019.05.037 UR - https://m2.mtmt.hu/api/publication/30750987 ID - 30750987 N1 - Funding text: We thank Zoltan Kele for mass spectrometry measurements, Eva TOthne Papp for synthesis contribution, and Attila Borics for helpful discussions. This research was supported by the grant K124952 of National Research Development and Innovation Office, and by the European Union co-financed by the European Regional Development Fund and the budget of Hungary (GINOP-2.3.2-15-2016-00060 entitled "Novel active pharmaceutical ingredients and their targeting with new carrier systems"). F.R.W. was supported by the Janos Bolyai Research Fellowship of the Hungarian Academy of Sciences and by the National Research, Development and Innovation Office, Hungary (PD-128480). AB - 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 LA - English DB - MTMT ER - TY - JOUR AU - Penke, Botond AU - Fülöp, Lívia AU - Szűcs, Mária AU - Frecska, Ede TI - The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases JF - CURRENT NEUROPHARMACOLOGY J2 - CURR NEUROPHARMACOL VL - 16 PY - 2018 IS - 1 SP - 97 EP - 116 PG - 20 SN - 1570-159X DO - 10.2174/1570159X15666170529104323 UR - https://m2.mtmt.hu/api/publication/3315334 ID - 3315334 N1 - Funding Agency and Grant Number: [KTIA_13_NAP-A-III/7]; [KTIA_13_NAP-A-II/7]; [GINOP-2.3.2-15-201600060] Funding text: This work was supported by the grants KTIA_13_NAP-A-III/7, KTIA_13_NAP-A-II/7 and GINOP-2.3.2-15-201600060. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Tarcsay, Ákos AU - Paragi, Gábor AU - Vass, Márton AU - Jójárt, Balázs AU - Bogár, Ferenc AU - Keserű, György Miklós TI - The Impact of Molecular Dynamics Sampling on the Performance of Virtual Screening against GPCRs JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING J2 - J CHEM INF MODEL VL - 53 PY - 2013 IS - 11 SP - 2990 EP - 2999 PG - 10 SN - 1549-9596 DO - 10.1021/ci400087b UR - https://m2.mtmt.hu/api/publication/2470032 ID - 2470032 N1 - Megjegyzés-26438826 Megjegyzés-23543048 FN: Thomson Reuters Web of Knowledge Megjegyzés-23563036 FN: Thomson Reuters Web of Knowledge Megjegyzés-23543047 FN: Thomson Reuters Web of Knowledge AB - 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. LA - English DB - MTMT ER -