@article{MTMT:32756662,
	title = {Electrophilic warheads in covalent drug discovery: an overview},
	url = {https://m2.mtmt.hu/api/publication/32756662},
	author = {Péczka, Nikolett and Orgován, Zoltán and Ábrányi-Balogh, Péter and Keserű, György Miklós},
	doi = {10.1080/17460441.2022.2034783},
	journal-iso = {EXPERT OPIN DRUG DIS},
	journal = {EXPERT OPINION ON DRUG DISCOVERY},
	volume = {17},
	unique-id = {32756662},
	issn = {1746-0441},
	year = {2022},
	eissn = {1746-045X},
	pages = {413-422}
}

@article{MTMT:32649994,
	title = {A covalent strategy to target intrinsically disordered proteins: Discovery of novel tau aggregation inhibitors},
	url = {https://m2.mtmt.hu/api/publication/32649994},
	author = {Petri, László and Ábrányi-Balogh, Péter and Vagrys, Darius and Imre, Timea and Varró, Nikolett and Mándity, István and Rácz, Anita and Wittner, Lucia and Tóth, Kinga and Tóth, Estilla Zsófia and Juhász, Tünde and Davis, Ben and Keserű, György Miklós},
	doi = {10.1016/j.ejmech.2022.114163},
	journal-iso = {EUR J MED CHEM},
	journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY},
	volume = {231},
	unique-id = {32649994},
	issn = {0223-5234},
	abstract = {Intrinsically disordered proteins (IDPs) play important roles in disease pathologies; however, their lack of defined stable 3D structures make traditional drug design strategies typically less effective against these targets. Based on promising results of targeted covalent inhibitors (TCIs) on challenging targets, we have developed a covalent design strategy targeting IDPs. As a model system we chose tau, an endogenous IDP of the central nervous system that is associated with severe neurodegenerative diseases via its aggregation. First, we mapped the tractability of available cysteines in tau and prioritized suitable warheads. Next, we introduced the selected vinylsulfone warhead to the non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders were synthesized and tested in aggregation models, and inhibited tau aggregation effectively. Our results revealed the usefulness of the covalent design strategy against therapeutically relevant IDP targets and provided promising candidates for the treatment of tauopathies.},
	year = {2022},
	eissn = {1768-3254},
	orcid-numbers = {Petri, László/0000-0001-9881-5096; Vagrys, Darius/0000-0002-8988-9787; Varró, Nikolett/0000-0003-4161-9021; Mándity, István/0000-0003-2865-6143; Wittner, Lucia/0000-0001-6800-0953; Tóth, Kinga/0000-0002-8751-8499}
}

@article{MTMT:31984014,
	title = {Discovery of selective fragment-sized immunoproteasome inhibitors},
	url = {https://m2.mtmt.hu/api/publication/31984014},
	author = {Kollár, Levente and Gobec, Martina and Szilágyi, Bence and Proj, Matic and Knez, Damijan and Ábrányi-Balogh, Péter and Petri, László and Imre, Timea and Bajusz, Dávid and Ferenczy, György and Gobec, Stanislav and Keserű, György Miklós and Sosič, Izidor},
	doi = {10.1016/j.ejmech.2021.113455},
	journal-iso = {EUR J MED CHEM},
	journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY},
	volume = {219},
	unique-id = {31984014},
	issn = {0223-5234},
	abstract = {Proteasomes contribute to maintaining protein homeostasis and their inhibition is beneficial in certain types of cancer and in autoimmune diseases. However, the inhibition of the proteasomes in healthy cells leads to unwanted side-effects and significant effort has been made to identify inhibitors specific for the immunoproteasome, especially to treat diseases which manifest increased levels and activity of this proteasome isoform. Here, we report our efforts to discover fragment-sized inhibitors of the human immunoproteasome. The screening of an in-house library of structurally diverse fragments resulted in the identification of benzo[d]oxazole-2(3H)-thiones, benzo[d]thiazole-2(3H)-thiones, benzo[d]imidazole-2(3H)-thiones, and 1-methylbenzo[d]imidazole-2(3H)-thiones (with a general term benzoXazole-2(3H)-thiones) as inhibitors of the chymotrypsin-like (β5i) subunit of the immunoproteasome. A subsequent structure-activity relationship study provided us with an insight regarding growing vectors. Binding to the β5i subunit was shown and selectivity against the β5 subunit of the constitutive proteasome was determined. Thorough characterization of these compounds suggested that they inhibit the immunoproteasome by forming a disulfide bond with the Cys48 available specifically in the β5i active site. To obtain fragments with biologically more tractable covalent interactions, we performed a warhead scan, which yielded benzoXazole-2-carbonitriles as promising starting points for the development of selective immunoproteasome inhibitors with non-peptidic scaffolds.},
	year = {2021},
	eissn = {1768-3254},
	orcid-numbers = {Petri, László/0000-0001-9881-5096; Bajusz, Dávid/0000-0003-4277-9481; Ferenczy, György/0000-0002-5771-4616; Gobec, Stanislav/0000-0002-9678-3083}
}

@article{MTMT:31848994,
	title = {WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors},
	url = {https://m2.mtmt.hu/api/publication/31848994},
	author = {Scarpino, Andrea and Petri, László and Knez, Damijan and Imre, Timea and Ábrányi-Balogh, Péter and Ferenczy, György and Gobec, Stanislav and Keserű, György Miklós},
	doi = {10.1007/s10822-020-00371-5},
	journal-iso = {J COMPUT AID MOL DES},
	journal = {JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN},
	volume = {35},
	unique-id = {31848994},
	issn = {0920-654X},
	abstract = {Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies the reactive docking method (Backus et al. in Nature 534:570–574, 2016) and extends it into a virtual screening tool by introducing facile experimental or computational parametrization and a ligand focused evaluation scheme together with a retrospective and prospective validation against various therapeutically relevant targets. Parameters accounting for ligand reactivity are derived from experimental reaction kinetic data or alternatively from computed reaction barriers. The performance of this docking protocol was first evaluated by investigating compound series with diverse warhead chemotypes against KRAS<jats:sup>G12C</jats:sup>, MurA and cathepsin B. In addition, WIDOCK was challenged on larger electrophilic libraries screened against OTUB2 and NUDT7. These retrospective analyses showed high sensitivity in retrieving experimental actives, by also leading to superior ROC curves, AUC values and better enrichments than the standard covalent docking tool available in AutoDock4 when compound collections with diverse warheads were investigated. Finally, we applied WIDOCK for the prospective identification of covalent human MAO-A inhibitors acting via a new mechanism by binding to Cys323. The inhibitory activity of several predicted compounds was experimentally confirmed and the labelling of Cys323 was proved by subsequent MS/MS measurements. These findings demonstrate the usefulness of WIDOCK as a warhead-sensitive, covalent virtual screening protocol.},
	year = {2021},
	eissn = {1573-4951},
	pages = {223-244},
	orcid-numbers = {Petri, László/0000-0001-9881-5096; Ferenczy, György/0000-0002-5771-4616; Keserű, György Miklós/0000-0003-1039-7809}
}

@article{MTMT:31699352,
	title = {Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease},
	url = {https://m2.mtmt.hu/api/publication/31699352},
	author = {Douangamath, Alice and Fearon, Daren and Gehrtz, Paul and Krojer, Tobias and Lukacik, Petra and Owen, C. David and Resnick, Efrat and Strain-Damerell, Claire and Aimon, Anthony and Ábrányi-Balogh, Péter and Brandao-Neto, Jose and Carbery, Anna and Davison, Gemma and Dias, Alexandre and Downes, Thomas D. and Dunnett, Louise and Fairhead, Michael and Firth, James D. and Jones, S. Paul and Keeley, Aaron Brian and Keserű, György Miklós and Klein, Hanna F. and Martin, Mathew P. and Noble, Martin E. M. and O'Brien, Peter and Powell, Ailsa and Reddi, Rambabu N. and Skyner, Rachael and Snee, Matthew and Waring, Michael J. and Wild, Conor and London, Nir and von Delft, Frank and Walsh, Martin A.},
	doi = {10.1038/s41467-020-18709-w},
	journal-iso = {NAT COMMUN},
	journal = {NATURE COMMUNICATIONS},
	volume = {11},
	unique-id = {31699352},
	abstract = {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.},
	year = {2020},
	eissn = {2041-1723},
	orcid-numbers = {Fearon, Daren/0000-0003-3529-7863; Aimon, Anthony/0000-0002-9135-129X; Ábrányi-Balogh, Péter/0000-0002-9284-5160; Keeley, Aaron Brian/0000-0002-3384-5945}
}

@article{MTMT:31428111,
	title = {Covalent fragment libraries in drug discovery},
	url = {https://m2.mtmt.hu/api/publication/31428111},
	author = {Keeley, Aaron Brian and Petri, László and Ábrányi-Balogh, Péter and Keserű, György Miklós},
	doi = {10.1016/j.drudis.2020.03.016},
	journal-iso = {DRUG DISCOV TODAY},
	journal = {DRUG DISCOVERY TODAY},
	volume = {25},
	unique-id = {31428111},
	issn = {1359-6446},
	abstract = {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.},
	year = {2020},
	eissn = {1878-5832},
	pages = {983-996},
	orcid-numbers = {Keeley, Aaron Brian/0000-0002-3384-5945; Petri, László/0000-0001-9881-5096; Ábrányi-Balogh, Péter/0000-0002-9284-5160}
}

@article{MTMT:31799316,
	title = {Affinity and Selectivity Assessment of Covalent Inhibitors by Free Energy Calculations},
	url = {https://m2.mtmt.hu/api/publication/31799316},
	author = {Mihalovits, Levente Márk and Ferenczy, György and Keserű, György Miklós},
	doi = {10.1021/acs.jcim.0c00834},
	journal-iso = {J CHEM INF MODEL},
	journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING},
	volume = {60},
	unique-id = {31799316},
	issn = {1549-9596},
	year = {2020},
	eissn = {1549-960X},
	pages = {6579-6594},
	orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Ferenczy, György/0000-0002-5771-4616}
}

@article{MTMT:31613727,
	title = {An electrophilic warhead library for mapping the reactivity and accessibility of tractable cysteines in protein kinases},
	url = {https://m2.mtmt.hu/api/publication/31613727},
	author = {Petri, László and Egyed, Attila and Bajusz, Dávid and Imre, Timea and Hetényi, Anasztázia and Martinek, Tamás and Ábrányi-Balogh, Péter and Keserű, György Miklós},
	doi = {10.1016/j.ejmech.2020.112836},
	journal-iso = {EUR J MED CHEM},
	journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY},
	volume = {207},
	unique-id = {31613727},
	issn = {0223-5234},
	year = {2020},
	eissn = {1768-3254},
	orcid-numbers = {Petri, László/0000-0001-9881-5096; Bajusz, Dávid/0000-0003-4277-9481; Hetényi, Anasztázia/0000-0001-8080-6992; Martinek, Tamás/0000-0003-3168-8066}
}

@article{MTMT:30590806,
	title = {Design and characterization of a heterocyclic electrophilic fragment library for the discovery of cysteine-targeted covalent inhibitors},
	url = {https://m2.mtmt.hu/api/publication/30590806},
	author = {Keeley, Aaron Brian and Ábrányi-Balogh, Péter and Keserű, György Miklós},
	doi = {10.1039/c8md00327k},
	journal-iso = {MEDCHEMCOMM},
	journal = {MEDCHEMCOMM},
	volume = {10},
	unique-id = {30590806},
	issn = {2040-2503},
	abstract = {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.},
	year = {2019},
	eissn = {2040-2511},
	pages = {263-267}
}

@article{MTMT:30334217,
	title = {A road map for prioritizing warheads for cysteine targeting covalent inhibitors},
	url = {https://m2.mtmt.hu/api/publication/30334217},
	author = {Ábrányi-Balogh, Péter and Petri, László and Imre, Timea and Szijj, Peter and Scarpino, Andrea and Hrast, Martina and Mitrovic, Ana and Fonovic, Ursa Petar and Németh, Krisztina and Barreteau, Helene and Roper, David I. and Horváti, Kata and Ferenczy, György and Kos, Janko and Ilas, Janez and Gobec, Stanislav and Keserű, György Miklós},
	doi = {10.1016/j.ejmech.2018.10.010},
	journal-iso = {EUR J MED CHEM},
	journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY},
	volume = {160},
	unique-id = {30334217},
	issn = {0223-5234},
	abstract = {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.},
	keywords = {SELECTIVITY; design; PROTEASES; CATHEPSIN-B; REACTIVITY; DRUG DISCOVERY; kinase inhibitors; cathepsin B; Covalent inhibitors; Electrophilic warheads; GSH reactivity assay; Oligopeptide specificity assay; MurA; MurA; ELECTROPHILES},
	year = {2018},
	eissn = {1768-3254},
	pages = {94-107},
	orcid-numbers = {Petri, László/0000-0001-9881-5096; Horváti, Kata/0000-0003-4092-6011; Ferenczy, György/0000-0002-5771-4616}
}