TY - JOUR AU - Péczka, Nikolett AU - Orgován, Zoltán AU - Ábrányi-Balogh, Péter AU - Keserű, György Miklós TI - Electrophilic warheads in covalent drug discovery: an overview JF - EXPERT OPINION ON DRUG DISCOVERY J2 - EXPERT OPIN DRUG DIS VL - 17 PY - 2022 SP - 413 EP - 422 PG - 10 SN - 1746-0441 DO - 10.1080/17460441.2022.2034783 UR - https://m2.mtmt.hu/api/publication/32756662 ID - 32756662 N1 - CAplus AN 2022:310212; MEDLINE PMID: 35129005 (Journal; General Review; Article); LA - English DB - MTMT ER - TY - JOUR AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Vagrys, Darius AU - Imre, Timea AU - Varró, Nikolett AU - Mándity, István AU - Rácz, Anita AU - Wittner, Lucia AU - Tóth, Kinga AU - Tóth, Estilla Zsófia AU - Juhász, Tünde AU - Davis, Ben AU - Keserű, György Miklós TI - A covalent strategy to target intrinsically disordered proteins: Discovery of novel tau aggregation inhibitors JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 231 PY - 2022 PG - 13 SN - 0223-5234 DO - 10.1016/j.ejmech.2022.114163 UR - https://m2.mtmt.hu/api/publication/32649994 ID - 32649994 LA - English DB - MTMT ER - TY - JOUR AU - Kollár, Levente AU - Gobec, Martina AU - Szilágyi, Bence AU - Proj, Matic AU - Knez, Damijan AU - Ábrányi-Balogh, Péter AU - Petri, László AU - Imre, Timea AU - Bajusz, Dávid AU - Ferenczy, György AU - Gobec, Stanislav AU - Keserű, György Miklós AU - Sosič, Izidor TI - Discovery of selective fragment-sized immunoproteasome inhibitors JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 219 PY - 2021 PG - 23 SN - 0223-5234 DO - 10.1016/j.ejmech.2021.113455 UR - https://m2.mtmt.hu/api/publication/31984014 ID - 31984014 LA - English DB - MTMT ER - TY - JOUR AU - Scarpino, Andrea AU - Petri, László AU - Knez, Damijan AU - Imre, Timea AU - Ábrányi-Balogh, Péter AU - Ferenczy, György AU - Gobec, Stanislav AU - Keserű, György Miklós TI - WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors JF - JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN J2 - J COMPUT AID MOL DES VL - 35 PY - 2021 IS - 2 SP - 223 EP - 244 PG - 22 SN - 0920-654X DO - 10.1007/s10822-020-00371-5 UR - https://m2.mtmt.hu/api/publication/31848994 ID - 31848994 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, 1117, Hungary Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana, 1000, Slovenia MS Metabolomic Research Laboratory, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, 1117, Hungary Export Date: 3 March 2021 CODEN: JCADE Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt 2, Hungary; email: keseru.gyorgy@ttk.hu Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, 1117, Hungary Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana, 1000, Slovenia MS Metabolomic Research Laboratory, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, 1117, Hungary Export Date: 4 March 2021 CODEN: JCADE Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt 2, Hungary; email: keseru.gyorgy@ttk.hu Funding details: Marie Curie Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, L1-8157, P1-0208, Z1-1859 Funding details: National Research, Development and Innovation Office, 2017-1.2.1-NKP-2017-00002, K111862, PD124598 Funding text 1: Open Access funding provided by ELKH Research Centre for Natural Sciences. This work has been supported by the Marie Sklodowska Curie Action (MSCA) Innovative Training Network grant FRAGNET, by the National Office for Research, Development and Innovation (2017-1.2.1-NKP-2017-00002, K111862 and PD124598 Grants), and by Slovenian Research Agency—ARRS (Grants Z1-1859, P1-0208 and L1-8157). LA - English DB - MTMT ER - TY - JOUR AU - Douangamath, Alice AU - Fearon, Daren AU - Gehrtz, Paul AU - Krojer, Tobias AU - Lukacik, Petra AU - Owen, C. David AU - Resnick, Efrat AU - Strain-Damerell, Claire AU - Aimon, Anthony AU - Ábrányi-Balogh, Péter AU - Brandao-Neto, Jose AU - Carbery, Anna AU - Davison, Gemma AU - Dias, Alexandre AU - Downes, Thomas D. AU - Dunnett, Louise AU - Fairhead, Michael AU - Firth, James D. AU - Jones, S. Paul AU - Keeley, Aaron Brian AU - Keserű, György Miklós AU - Klein, Hanna F. AU - Martin, Mathew P. AU - Noble, Martin E. M. AU - O'Brien, Peter AU - Powell, Ailsa AU - Reddi, Rambabu N. AU - Skyner, Rachael AU - Snee, Matthew AU - Waring, Michael J. AU - Wild, Conor AU - London, Nir AU - von Delft, Frank AU - Walsh, Martin A. TI - Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 11 PY - 2020 IS - 1 PG - 11 SN - 2041-1723 DO - 10.1038/s41467-020-18709-w UR - https://m2.mtmt.hu/api/publication/31699352 ID - 31699352 AB - COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease. LA - English DB - MTMT ER - TY - JOUR AU - Keeley, Aaron Brian AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Keserű, György Miklós TI - Covalent fragment libraries in drug discovery JF - DRUG DISCOVERY TODAY J2 - DRUG DISCOV TODAY VL - 25 PY - 2020 IS - 6 SP - 983 EP - 996 PG - 14 SN - 1359-6446 DO - 10.1016/j.drudis.2020.03.016 UR - https://m2.mtmt.hu/api/publication/31428111 ID - 31428111 AB - Targeted covalent inhibitors and chemical probes have become integral parts of drug discovery approaches. Given the advantages of fragment-based drug discovery, screening electrophilic fragments emerged as a promising alternative to discover and validate novel targets and to generate viable chemical starting points even for targets that are barely tractable. In this review, we present recent principles and considerations in the design of electrophilic fragment libraries from the selection of the appropriate covalent warhead through the design of the covalent fragment to the compilation of the library. We then summarize recent screening methodologies of covalent fragments against surrogate models, proteins, and the whole proteome, or living cells. Finally, we highlight recent drug discovery applications of covalent fragment libraries. LA - English DB - MTMT ER - TY - JOUR AU - Mihalovits, Levente Márk AU - Ferenczy, György AU - Keserű, György Miklós TI - Affinity and Selectivity Assessment of Covalent Inhibitors by Free Energy Calculations JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING J2 - J CHEM INF MODEL VL - 60 PY - 2020 IS - 12 SP - 6579 EP - 6594 PG - 16 SN - 1549-9596 DO - 10.1021/acs.jcim.0c00834 UR - https://m2.mtmt.hu/api/publication/31799316 ID - 31799316 LA - English DB - MTMT ER - TY - JOUR AU - Petri, László AU - Egyed, Attila AU - Bajusz, Dávid AU - Imre, Timea AU - Hetényi, Anasztázia AU - Martinek, Tamás AU - Ábrányi-Balogh, Péter AU - Keserű, György Miklós TI - An electrophilic warhead library for mapping the reactivity and accessibility of tractable cysteines in protein kinases JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 207 PY - 2020 PG - 9 SN - 0223-5234 DO - 10.1016/j.ejmech.2020.112836 UR - https://m2.mtmt.hu/api/publication/31613727 ID - 31613727 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary (NKFIH) [K116904]; Hungarian Science Foundation OTKA grantOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [PD124598]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences Funding text: This work was supported by the National Research, Development and Innovation Office of Hungary (NKFIH grant number K116904). P. Abranyi-Balogh was supported by the postdoctoral fellowship of the Hungarian Science Foundation OTKA (PD124598) grant. The work of D. Bajusz is supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. The authors are grateful to Balazs Mer}o (RCNS) for the expression of MELK, Zoltan Kele (SZTE) for his contribution to the MS investigation of MELK protein, Gyorgy G. Ferenczy (RCNS) and Greg Makara (ChemPass) for useful discussions on the manuscript. LA - English DB - MTMT ER - TY - JOUR AU - Keeley, Aaron Brian AU - Ábrányi-Balogh, Péter AU - Keserű, György Miklós TI - Design and characterization of a heterocyclic electrophilic fragment library for the discovery of cysteine-targeted covalent inhibitors JF - MEDCHEMCOMM J2 - MEDCHEMCOMM VL - 10 PY - 2019 SP - 263 EP - 267 PG - 5 SN - 2040-2503 DO - 10.1039/c8md00327k UR - https://m2.mtmt.hu/api/publication/30590806 ID - 30590806 AB - A fragment library of electrophilic small heterocycles was characterized through cysteine-reactivity and aqueous stability tests that suggested their potential as covalent warheads. The analysis of theoretical and experimental descriptors revealed correlations between the electronic properties of the heterocyclic cores and their reactivity against GSH that are helpful in identifying suitable fragments for cysteines with specific nucleophilicity. The most important advantage of these fragments is that they show only minimal structural differences from non-electrophilic counterparts. Therefore, they could be used effectively in the design of targeted covalent inhibitors with minimal influence on key non-covalent interactions. LA - English DB - MTMT ER - TY - JOUR AU - Ábrányi-Balogh, Péter AU - Petri, László AU - Imre, Timea AU - Szijj, Peter AU - Scarpino, Andrea AU - Hrast, Martina AU - Mitrovic, Ana AU - Fonovic, Ursa Petar AU - Németh, Krisztina AU - Barreteau, Helene AU - Roper, David I. AU - Horváti, Kata AU - Ferenczy, György AU - Kos, Janko AU - Ilas, Janez AU - Gobec, Stanislav AU - Keserű, György Miklós TI - A road map for prioritizing warheads for cysteine targeting covalent inhibitors JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 160 ET - 0 PY - 2018 SP - 94 EP - 107 PG - 14 SN - 0223-5234 DO - 10.1016/j.ejmech.2018.10.010 UR - https://m2.mtmt.hu/api/publication/30334217 ID - 30334217 N1 - Funding Agency and Grant Number: National Brain Research Program [KTIA NAP_13, 2017-1.2.1-NKP-2017-00002]; MSCA ETN FRAGNET [675899]; Hungarian Science Foundation OTKA [K116904]; Hungarian Academy of Sciences postdoctoral fellowship; Slovenian Research Agency [P4-0127, P1-0208, L1-6745]\n Funding text: This study was primarily supported by the National Brain Research Program grants (projects KTIA NAP_13 and project 2017-1.2.1-NKP-2017-00002) and MSCA ETN FRAGNET (project 675899) grant to G.M. Keseru. The project was also funded by the Hungarian Science Foundation OTKA (project K116904) and Hungarian Academy of Sciences postdoctoral fellowship to P. Abranyi-Balogh and Bolyai fellowship to K. Horvati. Additional support was provided by the Slovenian Research Agency (projects P4-0127, P1-0208 and L1-6745).\n Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt 2, Budapest, H-1117, Hungary MS Metabolomics Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt 2, Budapest, H-1117, Hungary Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana, SI-1000, Slovenia Chemical Biology Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt 2, Budapest, H-1117, Hungary Equipe Enveloppes Bactériennes et Antibiotiques, Institut de Biologie Intégrative de la Cellule (I2BC) UMR 9198 CEA-CNRS-UPSud, Université Paris-Sud, Bâtiment 430, ORSAY Cedex, F-91405, France School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, West Midlands CV4 7AL, United Kingdom MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Budapest, H-1117, Hungary Export Date: 3 January 2019 CODEN: EJMCA Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt 2, Hungary; email: keseru.gyorgy@ttk.mta.hu Chemicals/CAS: cysteine, 4371-52-2, 52-89-1, 52-90-4; glutathione, 70-18-8 Funding details: Hungarian Science Foundation, K116904 Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, L1-6745 Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, P1-0208 Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, P4-0127 Funding details: Magyar Tudományos Akadémia, MTA Funding details: 2017-1.2.1-NKP-2017-00002 Funding details: KTIA NAP_13 Funding details: 675899 Funding details: University of York Funding details: Universitat de Barcelona, UB Funding details: GlaxoSmithKline, GSK Funding text 1: This study was primarily supported by the National Brain Research Program grants (projects KTIA NAP_13 and project 2017-1.2.1-NKP-2017-00002 ) and MSCA ETN FRAGNET (project 675899 ) grant to G. M. Keserű. The project was also funded by the Hungarian Science Foundation OTKA (project K116904 ) and Hungarian Academy of Sciences postdoctoral fellowship to P. Ábrányi-Balogh and Bolyai fellowship to K. Horváti. Additional support was provided by the Slovenian Research Agency (projects P4-0127 , P1-0208 and L1-6745 ). Funding text 2: We thank I. Pápai (RCNS, Hungary), D. Menyhárd (ELTE, Hungary), G. Makara (ChemPass, Hungary), M. M. Hann (GlaxoSmithKline, UK), X. Barril (University of Barcelona, Spain) and R. Hubbard (University of York, UK) for their comments on the manuscript. Appendix A AB - Targeted covalent inhibitors have become an integral part of a number of therapeutic protocols and are the subject of intense research. The mechanism of action of these compounds involves the formation of a covalent bond with protein nucleophiles, mostly cysteines. Given the abundance of cysteines in the proteome, the specificity of the covalent inhibitors is of utmost importance and requires careful optimization of the applied warheads. In most of the cysteine targeting covalent inhibitor programs the design strategy involves incorporating Michael acceptors into a ligand that is already known to bind non-covalently. In contrast, we suggest that the reactive warhead itself should be tailored to the reactivity of the specific cysteine being targeted, and we describe a strategy to achieve this goal. Here, we have extended and systematically explored the available organic chemistry toolbox and characterized a large number of warheads representing different chemistries. We demonstrate that in addition to the common Michael addition, there are other nucleophilic addition, addition-elimination, nucleophilic substitution and oxidation reactions suitable for specific covalent protein modification. Importantly, we reveal that warheads for these chemistries impact the reactivity and specificity of covalent fragments at both protein and proteome levels. By integrating surrogate reactivity and selectivity models and subsequent protein assays, we define a road map to help enable new or largely unexplored covalent chemistries for the optimization of cysteine targeting inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved. LA - English DB - MTMT ER -