@article{MTMT:35478631, title = {Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential}, url = {https://m2.mtmt.hu/api/publication/35478631}, author = {Peter, Sonja and Siragusa, Lydia and Thomas, Morgan and Palomba, Tommaso and Cross, Simon and O’Boyle, Noel M. and Bajusz, Dávid and Ferenczy, György and Keserű, György Miklós and Bottegoni, Giovanni and Bender, Brian and Chen, Ijen and De Graaf, Chris}, doi = {10.1021/acs.jcim.4c00819}, journal-iso = {J CHEM INF MODEL}, journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING}, unique-id = {35478631}, issn = {1549-9596}, year = {2024}, eissn = {1549-960X}, orcid-numbers = {Peter, Sonja/0009-0009-6354-6979; Siragusa, Lydia/0000-0003-4596-7242; Bajusz, Dávid/0000-0003-4277-9481; Ferenczy, György/0000-0002-5771-4616; Bottegoni, Giovanni/0000-0003-1251-583X; Bender, Brian/0000-0001-9251-9480; Chen, Ijen/0000-0001-8865-3193; De Graaf, Chris/0000-0002-1226-2150} } @article{MTMT:35427664, title = {Target‐templated Construction of Functional Proteomimetics Using Photo‐foldamer Libraries}, url = {https://m2.mtmt.hu/api/publication/35427664}, author = {Wéber, Edit and Ábrányi-Balogh, Péter and Martinek, Tamas A. and Nagymihály, Bence and Karancsiné Menyhárd, Dóra and Péczka, Nikolett and Gadanecz, Márton and Schlosser, Gitta (Vácziné) and Orgován, Zoltán and Bogár, Ferenc and Bajusz, Dávid and Kecskeméti, Gábor and Szabó, Zoltán and Bartus, Éva and Tököli, Attila and Tóth, Gábor K. and Szalai, Tibor Viktor and Takács, Tamás and de Araujo, Elvin and Buday, László and Perczel, András and Keserű, György Miklós}, doi = {10.1002/ange.202410435}, journal-iso = {ANGEW CHEM}, journal = {ANGEWANDTE CHEMIE}, unique-id = {35427664}, issn = {0044-8249}, abstract = {Current methods for proteomimetic engineering rely on structure‐based design. Here we describe a design strategy that allows the construction of proteomimetics against challenging targets without a priori characterization of the target surface. Our approach relies on (i) a 100‐membered photoreactive foldamer library, the members of which act as local surface mimetics, and (ii) the subsequent affinity maturation of the primary hits using systems chemistry. Two surface‐oriented proteinogenic side chains drove the interactions between the short helical foldamer fragments and the proteins. Diazirine‐based photo‐crosslinking was applied to sensitively detected and localize binding even to shallow and dynamic patches on representatively difficult targets. Photo‐foldamers identified functionally relevant protein interfaces, allosteric and previously unexplored targetable regions on the surface of STAT3 and an oncogenic K‐Ras variant. Target‐templated dynamic linking of foldamer hits resulted in two orders of magnitude affinity improvement in a single step. The dimeric K‐Ras ligand mimicked protein‐like catalytic functions. The photo‐foldamer approach thus enables the highly efficient mapping of protein‐protein interaction sites and provides a viable starting point for proteomimetic ligand development without a priori structural hypotheses.}, year = {2024}, eissn = {1521-3757}, orcid-numbers = {Karancsiné Menyhárd, Dóra/0000-0002-0095-5531; Gadanecz, Márton/0009-0009-8076-7597; Schlosser, Gitta (Vácziné)/0000-0002-7637-7133; Bajusz, Dávid/0000-0003-4277-9481; Perczel, András/0000-0003-1252-6416} } @article{MTMT:35415397, title = {Exploring Chemical Spaces in the Billion Range: Is Docking a Computational Alternative to DNA-Encoded Libraries?}, url = {https://m2.mtmt.hu/api/publication/35415397}, author = {Mihalovits, Levente Márk and Szalai, Tibor Viktor and Bajusz, Dávid and Keserű, György Miklós}, doi = {10.1021/acs.jcim.4c00803}, journal-iso = {J CHEM INF MODEL}, journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING}, unique-id = {35415397}, issn = {1549-9596}, year = {2024}, eissn = {1549-960X}, orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Bajusz, Dávid/0000-0003-4277-9481} } @article{MTMT:35295180, title = {In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors}, url = {https://m2.mtmt.hu/api/publication/35295180}, author = {Maluck, Sara and Bobrovsky, Rivka and Poór, Miklós and Lange, Roman W. and Steinmetzer, Torsten and Jerzsele, Ákos and Adorján, András and Bajusz, Dávid and Rácz, Anita and Pásztiné Gere, Erzsébet}, doi = {10.3390/biomedicines12092075}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {12}, unique-id = {35295180}, abstract = {Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α1-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal activity in Madin–Darby canine kidney cells, especially compound MI-1851 at very low concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human hepatocytes also resulted in no changes in cell viability and oxidative stress at up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high concentrations. In conclusion, this study indicates a good safety profile of the furin inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for further in vivo investigations, despite some inhibitory effects on CYP3A4.}, year = {2024}, eissn = {2227-9059}, orcid-numbers = {Poór, Miklós/0000-0003-1425-7459; Lange, Roman W./0009-0004-7752-6403; Steinmetzer, Torsten/0000-0001-6523-4754; Jerzsele, Ákos/0000-0002-3380-0827; Adorján, András/0000-0002-2555-6123; Bajusz, Dávid/0000-0003-4277-9481} } @article{MTMT:35196297, title = {The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19}, url = {https://m2.mtmt.hu/api/publication/35196297}, author = {Papp, Henrietta and Tóth, Emese and Bovári-Biri, Judit and Bánfai, Krisztina and Juhász, Péter and Mahdi, M. and Russo, L.C. and Bajusz, Dávid and Sipos, Adrienn and Petri, László and Szalai, Tibor Viktor and Kemény, Ágnes and Madai, Mónika and Kuczmog, Anett and Batta, Gyula and Mózner, Orsolya and Vaskó, Dorottya and Hirsch, Edit and Bohus, P. and Méhes, Gábor and Tőzsér, József and Curtin, N.J. and Helyes, Zsuzsanna and Tóth, A. and Hoch, N.C. and Jakab, Ferenc and Keserű, György Miklós and Pongrácz, Judit and Bay, Péter}, doi = {10.1111/bph.17305}, journal-iso = {BR J PHARMACOL}, journal = {BRITISH JOURNAL OF PHARMACOLOGY}, unique-id = {35196297}, issn = {0007-1188}, abstract = {Background and Purpose: To date, there are limited options for severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus. As ADP-ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID-19. Experimental Approach: The effects of PARP inhibitors on virus uptake were assessed in cell-based experiments using multiple variants of SARS-CoV-2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti-inflammatory properties of rucaparib were demonstrated in cell-based models upon challenging with recombinant spike protein or SARS-CoV-2 RNA vaccine. Key Results: We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID-19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS-CoV-2 infection rate through binding to the conserved 493–498 amino acid region located in the spike-ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA-induced overexpression of cytokines was down-regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations. Conclusion and Implications: These results point towards repurposing rucaparib for treating inflammatory responses in COVID-19. © 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.}, keywords = {NFκB; rucaparib; ACE2; COVID-19; SARS-CoV-2 spike protein; SARS-CoV-2 RNA; viral lung inflammation}, year = {2024}, eissn = {1476-5381}, orcid-numbers = {Papp, Henrietta/0000-0003-3887-5657; Bajusz, Dávid/0000-0003-4277-9481; Petri, László/0000-0001-9881-5096; Kemény, Ágnes/0000-0002-4523-3938; Kuczmog, Anett/0000-0002-5680-4951; Batta, Gyula/0000-0002-0442-1828; Mózner, Orsolya/0000-0001-5784-7702; Vaskó, Dorottya/0000-0002-2502-0644; Pongrácz, Judit/0000-0002-0278-5556} } @article{MTMT:35160281, title = {Mapping protein binding sites by photoreactive fragment pharmacophores}, url = {https://m2.mtmt.hu/api/publication/35160281}, author = {Ábrányi-Balogh, Péter and Bajusz, Dávid and Orgován, Zoltán and Keeley, Aaron Brian and Petri, László and Péczka, Nikolett and Szalai, Tibor Viktor and Pálfy, Gyula and Gadanecz, Márton and Grant, Emma K. and Imre, Tímea and Takács, Tamás and Randelovic, Ivan and Baranyi, Marcell and Marton, András Dénes and Schlosser, Gitta (Vácziné) and Ashraf, Qirat F. and de Araujo, Elvin D. and Karancsi, Tamás and Buday, László and Tóvári, József and Perczel, András and Bush, Jacob T. and Keserű, György Miklós}, doi = {10.1038/s42004-024-01252-w}, journal-iso = {COMMUN CHEM}, journal = {COMMUNICATIONS CHEMISTRY}, volume = {7}, unique-id = {35160281}, issn = {2399-3669}, abstract = {Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRas G12D protein, and the yet unliganded N -terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. Our results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets.}, year = {2024}, eissn = {2399-3669}, orcid-numbers = {Bajusz, Dávid/0000-0003-4277-9481; Petri, László/0000-0001-9881-5096; Pálfy, Gyula/0000-0003-1590-5331; Gadanecz, Márton/0009-0009-8076-7597; Grant, Emma K./0009-0005-5229-9125; Randelovic, Ivan/0000-0003-0161-0022; Marton, András Dénes/0009-0008-5683-5484; Schlosser, Gitta (Vácziné)/0000-0002-7637-7133; de Araujo, Elvin D./0000-0003-0716-2830; Tóvári, József/0000-0002-5543-3204; Perczel, András/0000-0003-1252-6416; Bush, Jacob T./0000-0001-7165-0092} } @article{MTMT:35145349, title = {PK/PD investigation of antiviral host matriptase/TMPRSS2 inhibitors in cell models}, url = {https://m2.mtmt.hu/api/publication/35145349}, author = {Gamba, Dávid and van Eijk, Nicholas and Lányi, Katalin and Monostory, Katalin and Steinmetzer, Torsten and Marosi, András and Rácz, Anita and Bajusz, Dávid and Kruhl, Diana and Böttcher-Friebertshäuser, Eva and Pásztiné Gere, Erzsébet}, doi = {10.1038/s41598-024-67633-2}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {14}, unique-id = {35145349}, issn = {2045-2322}, abstract = {Certain corona- and influenza viruses utilize type II transmembrane serine proteases for cell entry, making these enzymes potential drug targets for the treatment of viral respiratory infections. In this study, the cytotoxicity and inhibitory effects of seven matriptase/TMPRSS2 inhibitors (MI-21, MI-463, MI-472, MI-485, MI-1900, MI-1903, and MI-1904) on cytochrome P450 enzymes were evaluated using fluorometric assays. Additionally, their antiviral activity against influenza A virus subtypes H1N1 and H9N2 was assessed. The metabolic depletion rates of these inhibitors in human primary hepatocytes were determined over a 120-min period by LC–MS/MS, and PK parameters were calculated. The tested compounds, with the exception of MI-21, displayed potent inhibition of CYP3A4, while all compounds lacked inhibitory effects on CYP1A2, CYP2C9, CYP2C19, and CYP2D6. The differences between the CYP3A4 activity within the series were rationalized by ligand docking. Elucidation of PK parameters showed that inhibitors MI-463, MI-472, MI-485, MI-1900 and MI-1904 were more stable compounds than MI-21 and MI-1903. Anti-H1N1 properties of inhibitors MI-463 and MI-1900 and anti-H9N2 effects of MI-463 were shown at 20 and 50 µM after 24 h incubation with the inhibitors, suggesting that these inhibitors can be applied to block entry of these viruses by suppressing host matriptase/TMPRSS2-mediated cleavage.}, year = {2024}, eissn = {2045-2322}, orcid-numbers = {Lányi, Katalin/0000-0003-1992-6324; Bajusz, Dávid/0000-0003-4277-9481} } @article{MTMT:34849934, title = {Alternative weighting schemes for fine‐tuned extended similarity indices}, url = {https://m2.mtmt.hu/api/publication/34849934}, author = {López Pérez, Kenneth and Rácz, Anita and Bajusz, Dávid and Gonzalez, Camila and Héberger, Károly and Miranda‐Quintana, Ramón Alain}, doi = {10.1002/cem.3558}, journal-iso = {J CHEMOMETR}, journal = {JOURNAL OF CHEMOMETRICS}, unique-id = {34849934}, issn = {0886-9383}, abstract = {Extended similarity indices (i.e., generalization of pairwise similarity) have recently gained importance because of their simplicity, fast computation, and superiority in tasks like diversity picking. However, they operate with several meta parameters that should be optimized. Earlier, we extended the binary similarity indices to “discrete non‐binary” and “continuous” data; now we continue with introducing and comparing multiple weighting functions. As a case study, the similarity of CYP enzyme inhibitors (4016 molecules after curation) was characterized by their extended similarities, based on 2D descriptors, MACCS and Morgan fingerprints. A statistical workflow based on sum of ranking differences (SRD) and analysis of variance (ANOVA) was used for finding the optimal weight function(s). Overall, the best weighting function is the fraction (“frac”), which corresponds to the principle of parsimony. Optimal extended similarity indices were also found, and their differences are revealed across different data sets. We intend this work to be a guideline for users of extended similarity indices regarding the various weighting options available. Source code for the calculations is available at https://github.com/mqcomplab/MultipleComparisons .}, year = {2024}, eissn = {1099-128X}, orcid-numbers = {Bajusz, Dávid/0000-0003-4277-9481} } @article{MTMT:34445373, title = {Electrophilic MiniFrags Revealed Unprecedented Binding Sites for Covalent HDAC8 Inhibitors}, url = {https://m2.mtmt.hu/api/publication/34445373}, author = {Keeley, Aaron Brian and Kopranovic, Aleksandra and Di Lorenzo, Vincenzo and Ábrányi-Balogh, Péter and Jänsch, Niklas and Lai, Linh N. and Petri, László and Orgován, Zoltán and Pölöske, Daniel and Orlova, Anna and Németh, András György and Desczyk, Charlotte and Imre, Timea and Bajusz, Dávid and Moriggl, Richard and Meyer-Almes, Franz-Josef and Keserű, György Miklós}, doi = {10.1021/acs.jmedchem.3c01779}, journal-iso = {J MED CHEM}, journal = {JOURNAL OF MEDICINAL CHEMISTRY}, volume = {67}, unique-id = {34445373}, issn = {0022-2623}, abstract = {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}, year = {2024}, eissn = {1520-4804}, pages = {572-585}, orcid-numbers = {Di Lorenzo, Vincenzo/0000-0002-3140-3561; Petri, László/0000-0001-9881-5096; Bajusz, Dávid/0000-0003-4277-9481; Meyer-Almes, Franz-Josef/0000-0002-1001-3249} } @article{MTMT:34223252, title = {Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones}, url = {https://m2.mtmt.hu/api/publication/34223252}, author = {Mihalovits, Levente Márk and Kollár, Levente and Bajusz, Dávid and Knez, Damijan and Bozovičar, Krištof and Imre, Timea and Ferenczy, György and Gobec, Stanislav and Keserű, György Miklós}, doi = {10.1002/cphc.202300596}, journal-iso = {CHEMPHYSCHEM}, journal = {CHEMPHYSCHEM: A EUROPEAN JOURNAL OF CHEMICAL PHYSICS AND PHYSICAL CHEMISTRY}, volume = {25}, unique-id = {34223252}, issn = {1439-4235}, abstract = {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.}, year = {2024}, eissn = {1439-7641}, orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Bajusz, Dávid/0000-0003-4277-9481; Ferenczy, György/0000-0002-5771-4616} }