TY - JOUR AU - Krámos, Balázs AU - Hadady, Zsuzsa AU - Makó, Attila AU - Szántó, Gábor AU - Felföldi, Nóra AU - Magdó, Ildikó AU - Bobok, Amrita Ágnes AU - Bata, Imre AU - Román, Viktor AU - Visegrády, András AU - Keserű, György Miklós AU - Greiner, István AU - Éles, János TI - Novel-Type GABA B PAMs: Structure–Activity Relationship in Light of the Protein Structure JF - ACS MEDICINAL CHEMISTRY LETTERS J2 - ACS MED CHEM LETT PY - 2024 SN - 1948-5875 DO - 10.1021/acsmedchemlett.3c00560 UR - https://m2.mtmt.hu/api/publication/34720633 ID - 34720633 LA - English DB - MTMT ER - TY - JOUR AU - Kollár, Levente AU - Grabrijan, Katarina AU - Hrast Rambaher, Martina AU - Bozovičar, Krištof AU - Imre, Tímea AU - Ferenczy, György AU - Gobec, Stanislav AU - Keserű, György Miklós TI - Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents JF - JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY J2 - J ENZYM INHIB MED CH VL - 39 PY - 2024 IS - 1 PG - 14 SN - 1475-6366 DO - 10.1080/14756366.2024.2305833 UR - https://m2.mtmt.hu/api/publication/34718013 ID - 34718013 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia MS Metabolomics Research Group, Research Centre for Natural Sciences, Budapest, Hungary Export Date: 8 March 2024 CODEN: JEIMA Correspondence Address: Keserű, G.M.; Department of Organic Chemistry and Technology, Műegyetem rkp. 3., Hungary; email: keseru.gyorgy@ttk.hu Funding details: RRF-2.3.1-21-2022-00015 Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, N1-0169, P1-0208 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, K135335 Funding details: Richter Gedeon Talentum Alapítvány Funding text 1: We thank Dr. Andrea Dessen (IBS, Grenoble) for donation of PBP1b plasmid and Dr. Pál Szabó for HRMS measurements. This study was supported by National Research, Development and Innovation Office Grants K135335, and by the National Drug Research and Development Laboratory (PharmaLab) project (RRF-2.3.1-21-2022-00015). Funding text 2: This research was funded by the National Research Development and Innovation Office (Grant Numbers: SNN 135335), Slovenian Research Agency (ARRS) Research Core Funding P1-0208, grant N1-0169 and a PhD grant to K.G. L.K. is supported by the Gedeon Richter Talentum Foundation and the József Varga Foundation and Javna Agencija za Raziskovalno Dejavnost RS. We thank Dr. Andrea Dessen (IBS, Grenoble) for donation of PBP1b plasmid and Dr. Pál Szabó for HRMS measurements. This study was supported by National Research, Development and Innovation Office Grants K135335, and by the National Drug Research and Development Laboratory (PharmaLab) project (RRF-2.3.1-21-2022-00015). LA - English DB - MTMT ER - TY - CHAP AU - Mihalovits, Levente Márk AU - Ferenczy, György AU - Keserű, György Miklós ED - Ramaswamy, Vijayan ED - Poongavanam, Vasanthanathan TI - Free Energy Calculations in Covalent Drug Design T2 - Computational Drug Discovery PB - Wiley SN - 9783527840748 PY - 2024 SP - 561 EP - 578 PG - 18 DO - 10.1002/9783527840748.ch23 UR - https://m2.mtmt.hu/api/publication/34535308 ID - 34535308 LA - English DB - MTMT ER - TY - JOUR AU - Németh, András György AU - Kollár, Levente AU - Németh, K. AU - Schlosser, Gitta (Vácziné) AU - Minus, Annamária AU - Keserű, György Miklós TI - On-DNA Synthesis of Multisubstituted Indoles JF - ORGANIC LETTERS J2 - ORG LETT VL - 26 PY - 2024 IS - 13 SP - 2517 EP - 2522 PG - 6 SN - 1523-7060 DO - 10.1021/acs.orglett.3c03602 UR - https://m2.mtmt.hu/api/publication/34492242 ID - 34492242 N1 - Export Date: 10 January 2024; Cited By: 0; Correspondence Address: G.M. Keserű; Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, H-1117, Hungary; email: keseru.gyorgy@ttk.hu; CODEN: ORLEF AB - The increasing role of the DNA-encoded library technology in early phase drug discovery represents a significant demand for DNA-compatible synthetic methods for therapeutically relevant heterocycles. Herein, we report the first on-DNA synthesis of multisubstituted indoles via a cascade reaction of Sonogashira coupling and intramolecular ring closure. Further functionalization by Suzuki coupling at the third position exploits a diverse chemical space. The high fidelity of the method also enabled the construction of an indole-based mock library. © 2023 The Authors. Published by American Chemical Society. LA - English DB - MTMT ER - TY - JOUR AU - Keeley, Aaron Brian AU - Kopranovic, Aleksandra AU - Di Lorenzo, Vincenzo AU - Ábrányi-Balogh, Péter AU - Jänsch, Niklas AU - Lai, Linh N. AU - Petri, László AU - Orgován, Zoltán AU - Pölöske, Daniel AU - Orlova, Anna AU - Németh, András György AU - Desczyk, Charlotte AU - Imre, Timea AU - Bajusz, Dávid AU - Moriggl, Richard AU - Meyer-Almes, Franz-Josef AU - Keserű, György Miklós TI - Electrophilic MiniFrags Revealed Unprecedented Binding Sites for Covalent HDAC8 Inhibitors JF - JOURNAL OF MEDICINAL CHEMISTRY J2 - J MED CHEM VL - 67 PY - 2024 IS - 1 SP - 572 EP - 585 PG - 14 SN - 0022-2623 DO - 10.1021/acs.jmedchem.3c01779 UR - https://m2.mtmt.hu/api/publication/34445373 ID - 34445373 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, H-1117, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Müegyetem rkp. 3., Budapest, H-1111, Hungary National Laboratory for Drug Research and Development, Budapest, H-1117, Hungary Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, Darmstadt, 64295, Germany Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210, Austria MS Metabolomics Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, H-1117, Hungary Export Date: 14 March 2024 CODEN: JMCMA Correspondence Address: Meyer-Almes, F.-J.; Department of Chemical Engineering and Biotechnology, Haardtring 100, Germany; email: franz-josef.meyer-almes@h-da.de Correspondence Address: Keserü, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt 2, Hungary; email: keseru.gyorgy@ttk.hu AB - Screening of ultra-low-molecular weight ligands (MiniFrags) successfully identified viable chemical starting points for a variety of drug targets. Here we report the electrophilic analogues of MiniFrags that allow the mapping of potential binding sites for covalent inhibitors by biochemical screening and mass spectrometry. Small electrophilic heterocycles and their N-quaternized analogues were first characterized in the glutathione assay to analyze their electrophilic reactivity. Next, the library was used for systematic mapping of potential covalent binding sites available in human histone deacetylase 8 (HDAC8). The covalent labeling of HDAC8 cysteines has been proven by tandem mass spectrometry measurements, and the observations were explained by mutating HDAC8 cysteines. As a result, screening of electrophilic MiniFrags identified three potential binding sites suitable for the development of allosteric covalent HDAC8 inhibitors. One of the hit fragments was merged with a known HDAC8 inhibitor fragment using different linkers, and the linker length was optimized to result in a lead-like covalent inhibitor. © 2023 The Authors. Published by American Chemical Society LA - English DB - MTMT ER - TY - JOUR AU - Pándy-Szekeres, Gáspár AU - Taracena Herrera, Luis P AU - Caroli, Jimmy AU - Kermani, Ali A AU - Kulkarni, Yashraj AU - Keserű, György Miklós AU - Gloriam, David E TI - GproteinDb in 2024: new G protein-GPCR couplings, AlphaFold2-multimer models and interface interactions JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 52 PY - 2024 IS - D1 SP - D466 EP - D475 SN - 0305-1048 DO - 10.1093/nar/gkad1089 UR - https://m2.mtmt.hu/api/publication/34405999 ID - 34405999 AB - G proteins are the major signal proteins of ∼800 receptors for medicines, hormones, neurotransmitters, tastants and odorants. GproteinDb offers integrated genomic, structural, and pharmacological data and tools for analysis, visualization and experiment design. Here, we present the first major update of GproteinDb greatly expanding its coupling data and structural templates, adding AlphaFold2 structure models of GPCR–G protein complexes and advancing the interactive analysis tools for their interfaces underlying coupling selectivity. We present insights on coupling agreement across datasets and parameters, including constitutive activity, agonist-induced activity and kinetics. GproteinDb is accessible at https://gproteindb.org. LA - English DB - MTMT ER - TY - JOUR AU - Mihalovits, Levente Márk AU - Kollár, Levente AU - Bajusz, Dávid AU - Knez, Damijan AU - Bozovičar, Krištof AU - Imre, Timea AU - Ferenczy, György AU - Gobec, Stanislav AU - Keserű, György Miklós TI - Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones JF - CHEMPHYSCHEM: A EUROPEAN JOURNAL OF CHEMICAL PHYSICS AND PHYSICAL CHEMISTRY J2 - CHEMPHYSCHEM VL - 25 PY - 2024 IS - 1 SN - 1439-4235 DO - 10.1002/cphc.202300596 UR - https://m2.mtmt.hu/api/publication/34223252 ID - 34223252 N1 - Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3., Budapest, 1111, Hungary Department of Medicinal Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia MS Metabolomics Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary Export Date: 24 November 2023 CODEN: CPCHF Correspondence Address: Bajusz, D.; Medicinal Chemistry Research Group, Magyar tudósok krt. 2, Hungary; email: bajusz.david@ttk.hu Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt. 2, Hungary; email: keseru.gyorgy@ttk.hu AB - Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS‐CoV‐2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in‐house, cysteine‐targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules. LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Kontra, Bence AU - Chiovini, Balázs AU - Müller, Dalma AU - Tóth, Estilla Zsófia AU - Ábrányi-Balogh, Péter AU - Wittner, Lucia AU - Várady, György AU - Turczel, Gábor AU - Farkas, Ödön AU - Owen, Michael Christopher AU - Katona, Gergely AU - Győrffy, Balázs AU - Keserű, György Miklós AU - Mucsi, Zoltán AU - Rózsa J., Balázs AU - Kovács, Ervin TI - Effective Synthesis, Development and Application of a Highly Fluorescent Cyanine Dye for Antibody Conjugation and Microscopy Imaging JF - ORGANIC & BIOMOLECULAR CHEMISTRY J2 - ORG BIOMOL CHEM VL - 21 PY - 2023 IS - 44 SP - 8829 EP - 8836 PG - 8 SN - 1477-0520 DO - 10.1039/D3OB01471A UR - https://m2.mtmt.hu/api/publication/34205650 ID - 34205650 AB - An asymmetric cyanine-type fluorescent dye was designed and synthesized via a versatile, multi-step process, aiming to conjugate with an Her2+ receptor specific antibody by an azide-alkyne click reaction. The aromaticity and the excitation and relaxation energetics of the fluorophore were characterized by computational methods. The synthesized dye exhibited excellent fluorescence properties for confocal microscopy, offering efficient applicability in in vitro imaging due to its merits such as a high molar absorption coefficient (36 816 M-1 cm-1), excellent brightness, optimal wavelength (627 nm), larger Stokes shift (26 nm) and appropriate photostability compared to cyanines. The conjugated cyanine-trastuzumab was constructed via an effective, metal-free, strain-promoted azide-alkyne click reaction leading to a regulated number of dyes being conjugated. This novel cyanine-labelled antibody was successfully applied for in vitro confocal imaging and flow cytometry of Her2+ tumor cells. An azido cyanine dye was synthesized and characterized by computational and experimental techniques and applied in tumor cell imaging. LA - English DB - MTMT ER - TY - JOUR AU - Csorba, Noémi AU - Ábrányi-Balogh, Péter AU - Keserű, György Miklós TI - Covalent fragment approaches targeting non-cysteine residues JF - TRENDS IN PHARMACOLOGICAL SCIENCES J2 - TRENDS PHARMACOL SCI VL - 44 PY - 2023 IS - 11 SP - 802 EP - 816 PG - 15 SN - 0165-6147 DO - 10.1016/j.tips.2023.08.014 UR - https://m2.mtmt.hu/api/publication/34160949 ID - 34160949 N1 - Export Date: 6 October 2023 CODEN: TPHSD Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt. 2, 1117, Hungary; email: keseru.gyorgy@ttk.hu LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Chiovini, Balázs AU - Müller, Dalma AU - Tóth, Estilla Zsófia AU - Fülöp, Anna AU - Ábrányi-Balogh, Péter AU - Wittner, Lucia AU - Várady, György AU - Farkas, Ödön AU - Turczel, Gábor AU - Katona, Gergely AU - Győrffy, Balázs AU - Keserű, György Miklós AU - Mucsi, Zoltán AU - Rózsa J., Balázs AU - Kovács, Ervin TI - Synthesis and Application of Two-Photon Active Fluorescent Rhodol Dyes for Antibody Conjugation and In Vitro Cell Imaging JF - ACS OMEGA J2 - ACS OMEGA VL - 8 PY - 2023 IS - 25 SP - 22836 EP - 22843 PG - 8 SN - 2470-1343 DO - 10.1021/acsomega.3c01796 UR - https://m2.mtmt.hu/api/publication/34015800 ID - 34015800 LA - English DB - MTMT ER - TY - JOUR AU - Bajusz, Dávid AU - Pándy-Szekeres, Gáspár AU - Takács, Ágnes AU - de Araujo, Elvin D AU - Keserű, György Miklós TI - SH2db, an information system for the SH2 domain JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 51 PY - 2023 IS - W1 SP - W542 EP - W552 SN - 0305-1048 DO - 10.1093/nar/gkad420 UR - https://m2.mtmt.hu/api/publication/33845452 ID - 33845452 N1 - Funding Agency and Grant Number: MSCA ITN ALLODD [956314]; National Research Development and Innovation Office of Hungary [K135150, RRF-2.3.1-21-2022-00015]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-22-5]; MSCA [956314, K135150] Funding text: MSCA ITN ALLODD [956314 to G.M.K.]; National Research Development and Innovation Office of Hungary [K135150, PharmaLab (RRF-2.3.1-21-2022-00015)]; the work of D.B. was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences and the 'UNKP-22-5 New National Excellence Program of the Ministry for Innovation and Technology. FUNDING for open access charge: MSCA-funded project 'ALLODD' [956314] and NRDIO grant [K135150]. AB - SH2 domains are key mediators of phosphotyrosine-based signalling, and therapeutic targets for diverse, mostly oncological, disease indications. They have a highly conserved structure with a central beta sheet that divides the binding surface of the protein into two main pockets, responsible for phosphotyrosine binding (pY pocket) and substrate specificity (pY + 3 pocket). In recent years, structural databases have proven to be invaluable resources for the drug discovery community, as they contain highly relevant and up-to-date information on important protein classes. Here, we present SH2db, a comprehensive structural database and webserver for SH2 domain structures. To organize these protein structures efficiently, we introduce (i) a generic residue numbering scheme to enhance the comparability of different SH2 domains, (ii) a structure-based multiple sequence alignment of all 120 human wild-type SH2 domain sequences and their PDB and AlphaFold structures. The aligned sequences and structures can be searched, browsed and downloaded from the online interface of SH2db (http://sh2db.ttk.hu), with functions to conveniently prepare multiple structures into a Pymol session, and to export simple charts on the contents of the database. Our hope is that SH2db can assist researchers in their day-to-day work by becoming a one-stop shop for SH2 domain related research. LA - English DB - MTMT ER - TY - JOUR AU - Godoy, Andre Schutzer AU - Nakamura, Aline Minalli AU - Douangamath, Alice AU - Song, Yun AU - Noske, Gabriela Dias AU - Gawriljuk, Victor Oliveira AU - Fernandes, Rafaela Sachetto AU - Pereira, Humberto D Muniz AU - Oliveira, Ketllyn Irene Zagato AU - Fearon, Daren AU - Dias, Alexandre AU - Krojer, Tobias AU - Fairhead, Michael AU - Powell, Alisa AU - Dunnet, Louise AU - Brandao-Neto, Jose AU - Skyner, Rachael AU - Chalk, Rod AU - Bajusz, Dávid AU - Bege, Miklós AU - Borbás, Anikó AU - Keserű, György Miklós AU - von Delft, Frank AU - Oliva, Glaucius TI - Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 51 PY - 2023 IS - 10 SP - 5255 EP - 5270 PG - 16 SN - 0305-1048 DO - 10.1093/nar/gkad314 UR - https://m2.mtmt.hu/api/publication/33802561 ID - 33802561 AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to evade the immune system. NendoU is a promising target for the development of new antiviral drugs. However, the complexity of the enzyme's structure and kinetics, along with the broad range of recognition sequences and lack of structural complexes, hampers the development of inhibitors. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of manganese on enzymatic activity. Through combining cryo-electron microscopy at different pHs, X-ray crystallography and biochemical and structural analysis, we showed that NendoU can shift between open and closed forms, which probably correspond to active and inactive states, respectively. We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. Overall, our findings provide insights into the complex structure and function of NendoU and offer new opportunities for the development of inhibitors. LA - English DB - MTMT ER - TY - JOUR AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Csorba, Noémi AU - Keeley, Aaron Brian AU - Simon, József AU - Randelovic, Ivan AU - Tóvári, József AU - Schlosser, Gitta (Vácziné) AU - Szabó, Dániel AU - Drahos, László AU - Keserű, György Miklós TI - Activation-Free Sulfonyl Fluoride Probes for Fragment Screening JF - MOLECULES J2 - MOLECULES VL - 28 PY - 2023 IS - 7 PG - 17 SN - 1420-3049 DO - 10.3390/molecules28073042 UR - https://m2.mtmt.hu/api/publication/33729477 ID - 33729477 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary National Laboratory for Drug Research and Development, Research Centre for Natural Sciences, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Szent Gellért tér 4, Budapest, 1111, Hungary Research Centre for Natural Sciences, MS Metabolomics Research Group, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary KINETO Lab Ltd, Zápor u. 55, Budapest, 1032, Hungary Department of Experimental Pharmacology and National Tumor Biology Laboratory, National Institute of Oncology, POB 21, Budapest, 1525, Hungary MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Institute of Chemistry, ELTE Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, 1117, Hungary MS Proteomics Research Group, Research Centre for Natural Sciences, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary Cited By :3 Export Date: 13 March 2024 CODEN: MOLEF Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar Tudósok Krt. 2, Hungary; email: keseru.gyorgy@ttk.hu AB - SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Accordingly, sulfonyl fluorides label multiple nucleophilic amino acid residues, making these reagents popular in both chemical biology and medicinal chemistry applications. The reactivity of sulfonyl fluorides nominates this warhead chemotype as a candidate for an external, activation-free general labelling tag. Here, we report the synthesis and characterization of a small sulfonyl fluoride library that yielded the 3-carboxybenzenesulfonyl fluoride warhead for tagging tractable targets at nucleophilic residues. Based on these results, we propose that coupling diverse fragments to this warhead would result in a library of sulfonyl fluoride bits (SuFBits), available for screening against protein targets. SuFBits will label the target if it binds to the core fragment, which facilitates the identification of weak fragments by mass spectrometry. LA - English DB - MTMT ER - TY - JOUR AU - Orgován, Zoltán AU - Péczka, Nikolett AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Randelovic, Ivan AU - Tóth, Szilárd AU - Szakács, Gergely AU - Nyíri, Kinga AU - Vértessy, Beáta (Grolmuszné) AU - Pálfy, Gyula AU - Vida, István AU - Perczel, András AU - Tóvári, József AU - Keserű, György Miklós TI - Covalent fragment mapping of KRasG12C revealed novel chemotypes with in vivo potency JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 250 PY - 2023 PG - 7 SN - 0223-5234 DO - 10.1016/j.ejmech.2023.115212 UR - https://m2.mtmt.hu/api/publication/33647485 ID - 33647485 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary KINETO Lab Ltd, Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Hungary Laboratory of Structural Chemistry and Biology, Eötvös Loránd University, Budapest, Hungary MTA-ELTE Protein Modelling Research Group, Eötvös Loránd University, Budapest, Hungary Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary CODEN: EJMCA Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, 2 Magyar tudósok kӧrútja, Hungary; email: keseru.gyorgy@ttk.hu AB - G12C mutant KRas is considered druggable by allele-specific covalent inhibitors due to the nucleophilic character of the oncogenic mutant cysteine at position 12. Discovery of these inhibitors requires the optimization of both covalent and noncovalent interactions. Here, we report covalent fragment screening of our electrophilic fragment library of diverse non-covalent scaffolds equipped with 40 different electrophilic functionalities to identify fragments as suitable starting points targeting Cys12. Screening the library against KRasG12C using Ellman's free thiol assay, followed by protein NMR and cell viability assays, resulted in two potential inhibitor chemotypes. Characterization of these scaffolds in in vitro cellular- and in vivo xenograft models revealed them as promising starting points for covalent drug discovery programs. LA - English DB - MTMT ER - TY - JOUR AU - Pándy-Szekeres, Gáspár AU - Caroli, Jimmy AU - Mamyrbekov, Alibek AU - Kermani, Ali A. AU - Keserű, György Miklós AU - Kooistra, Albert J. AU - Gloriam, David E. TI - GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 51 PY - 2023 IS - D1 SP - D395 EP - D402 PG - 8 SN - 0305-1048 DO - 10.1093/nar/gkac1013 UR - https://m2.mtmt.hu/api/publication/33421768 ID - 33421768 AB - G protein-coupled receptors (GPCRs) are physiologically abundant signaling hubs routing hundreds of extracellular signal substances and drugs into intracellular pathways. The GPCR database, GPCRdb supports > 5000 interdisciplinary researchers every month with reference data, analysis, visualization, experiment design and dissemination. Here, we present our fifth major GPCRdb release setting out with an overview of the many resources for receptor sequences, structures, and ligands. This includes recently published additions of class D generic residue numbers, a comparative structure analysis tool to identify functional determinants, trees clustering GPCR structures by 3D conformation, and mutations stabilizing inactive/active states. We provide new state-specific structure models of all human non-olfactory GPCRs built using AlphaFold2-MultiState. We also provide a new resource of endogenous ligands along with a larger number of surrogate ligands with bioactivity, vendor, and physiochemical descriptor data. The one-stop-shop ligand resources integrate ligands/data from the ChEMBL, Guide to Pharmacology, PDSP Ki and PubChem database. The GPCRdb is available athttps://gpcrdb.org. LA - English DB - MTMT ER - TY - JOUR AU - Szilágyi, Bence AU - Egyed, Attila AU - Mándity, István AU - Nagy, Tamás AU - Kátainé Fadgyas, Katalin AU - Volk, Balázs AU - Keserű György, M. TI - Safe and Efficient Continuous-Flow Synthesis and Batchwise Hydrolysis of Ethyl 5-Acetyl-1H-pyrazole-3-carboxylate: A Key Synthon of Darolutamide JF - SYNTHESIS-STUTTGART J2 - SYNTHESIS-STUTTGART VL - 55 PY - 2023 IS - 6 SP - 959 EP - 966 PG - 8 SN - 0039-7881 DO - 10.1055/s-0042-1751389 UR - https://m2.mtmt.hu/api/publication/33283298 ID - 33283298 LA - English DB - MTMT ER - TY - JOUR AU - Mihalovits, Levente Márk AU - Ferenczy, György AU - Keserű, György Miklós TI - A kovalens enziminhibíció számításos kémiai jellemzése JF - MAGYAR KÉMIAI FOLYÓIRAT - KÉMIAI KÖZLEMÉNYEK (1997-) J2 - MAGY KÉM FOLY KÉM KÖZL VL - 128 PY - 2022 IS - 3-4 SP - 150 EP - 156 PG - 7 SN - 1418-9933 DO - 10.24100/MKF.2022.03-4.150 UR - https://m2.mtmt.hu/api/publication/33543903 ID - 33543903 N1 - "Mihalovits Levente Márk Computational characterization of covalent enzyme inhibition című PhD értekezéséhez kapcsolódó tézisfüzet alapján készült." LA - Hungarian DB - MTMT ER - TY - JOUR AU - Mayer, Szabolcs AU - Nagy, Nóra AU - Keglevich, Péter AU - Ábrányi-Balogh, Péter AU - Hazai, László TI - Sejtosztódásgátló hatású vindolin- és flavonoidszármazékok előállítása JF - MAGYAR KÉMIAI FOLYÓIRAT - KÉMIAI KÖZLEMÉNYEK (1997-) J2 - MAGY KÉM FOLY KÉM KÖZL VL - 128 PY - 2022 IS - 3-4 SP - 137 EP - 142 PG - 6 SN - 1418-9933 DO - 10.24100/MKF.2022.03-4.137 UR - https://m2.mtmt.hu/api/publication/33543663 ID - 33543663 N1 - "Mayer Szabolcs PhD értekezéséhez kapcsolódó tézisfüzet alapján készült." LA - Hungarian DB - MTMT ER - TY - JOUR AU - Kiss-Szemán, Anna Júlia AU - Takács, Luca AU - Orgován, Zoltán AU - Stráner, Pál AU - Jákli, Imre AU - Schlosser, Gitta (Vácziné) AU - Masiulis, Simonas AU - Harmat, Veronika AU - Karancsiné Menyhárd, Dóra AU - Perczel, András TI - A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase–meropenem complex JF - CHEMICAL SCIENCE J2 - CHEM SCI VL - 13 PY - 2022 IS - 48 SP - 14264 EP - 14276 PG - 13 SN - 2041-6520 DO - 10.1039/D2SC05520A UR - https://m2.mtmt.hu/api/publication/33307131 ID - 33307131 N1 - Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, Hungary Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary ELKH-ELTE Protein Modelling Research Group, Eötvös Loránd Research Network, Budapest, Hungary ELKH-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary Materials and Structural Analysis Division, Thermo Fisher Scientific, Eindhoven, Netherlands Export Date: 28 March 2023 CODEN: CSHCC Correspondence Address: Harmat, V.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Hungary; email: veronika.harmat@ttk.elte.hu Correspondence Address: Menyhárd, D.K.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Hungary; email: dora.k.menyhard@ttk.elte.hu Correspondence Address: Perczel, A.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Hungary; email: perczel.andras@ttk.elte.hu AB - The structure of porcine AAP (pAAP) in a covalently bound complex with meropenem was determined by cryo-EM to 2.1 Å resolution, showing the mammalian serine-protease inhibited by a carbapenem antibiotic. LA - English DB - MTMT ER - TY - JOUR AU - Ábrányi-Balogh, Péter AU - Keeley, Aaron AU - Ferenczy, György AU - Petri, László AU - Imre, Timea AU - Grabrijan, Katarina AU - Hrast, Martina AU - Knez, Damijan AU - Ilaš, Janez AU - Gobec, Stanislav AU - Keserű, György Miklós TI - Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors JF - PHARMACEUTICALS J2 - PHARMACEUTICALS-BASE VL - 15 PY - 2022 IS - 12 SN - 1424-8247 DO - 10.3390/ph15121484 UR - https://m2.mtmt.hu/api/publication/33298396 ID - 33298396 AB - Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocyclic electrophiles: the quaternized analogue of the heterocyclic covalent fragment library with improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH (L-glutathione) reactivity assay, and thrombin counter screen were also used to demonstrate and explain the improved reactivity and selectivity of the N-methylated heterocycles and to compare the two generations of heterocyclic electrophiles. LA - English DB - MTMT ER -