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 - 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 - Mihalovits, Levente Márk AU - Ferenczy, György AU - Keserű, György Miklós TI - The role of quantum chemistry in covalent inhibitor design JF - INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY J2 - INT J QUANTUM CHEM VL - 122 PY - 2022 IS - 8 PG - 17 SN - 0020-7608 DO - 10.1002/qua.26768 UR - https://m2.mtmt.hu/api/publication/32298744 ID - 32298744 N1 - Funding Agency and Grant Number: Nemzeti Kutatasi Fejlesztesi es Innovacios HivatalNational Research, Development & Innovation Office (NRDIO) - Hungary [SNN 125496, SNN 135335] Funding text: Nemzeti Kutatasi Fejlesztesi es Innovacios Hivatal, Grant/Award Numbers: SNN 125496, SNN 135335 AB - The recent ascent of targeted covalent inhibitors (TCI) in drug discovery brings new opportunities and challenges to quantum chemical reactivity calculations supporting discovery efforts. TCIs typically form a covalent bond with the targeted nucleophilic amino acid side chain. Their reactivity that can be both computed and experimentally measured is therefore one of the key factors in determining inhibitory potency. Calculation of relevant quantum chemical descriptors and corresponding reaction barriers of model reactions represent efficient ways to predict intrinsic reactivities of covalent ligands. A more comprehensive description of covalent ligand binding is offered by mixed quantum mechanical/molecular mechanical (QM/MM) potentials. Reaction mechanisms can be investigated by the exploration of the potential energy surface as a function of suitable reaction coordinates, and free energy surfaces can also be calculated with molecular dynamics based simulations. Here we review the methodological aspects and discuss applications with primary focus on high-end QM/MM simulations to illustrate the current status of quantum chemical support to covalent inhibitor design. Available QM approaches are suitable to identify likely reaction mechanisms and rate determining steps in the binding of covalent inhibitors. The efficient QM/MM prediction of ligand reactivities complemented with the computational description of the recognition step makes these computations highly useful in covalent drug discovery. 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 - Rácz, Anita AU - Mihalovits, Levente Márk AU - Bajusz, Dávid AU - Héberger, Károly AU - Miranda-Quintana, Ramón Alain TI - Molecular Dynamics Simulations and Diversity Selection by Extended Continuous Similarity Indices JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING J2 - J CHEM INF MODEL VL - 62 PY - 2022 IS - 14 SP - 3415 EP - 3425 PG - 11 SN - 1549-9596 DO - 10.1021/acs.jcim.2c00433 UR - https://m2.mtmt.hu/api/publication/32992489 ID - 32992489 LA - English DB - MTMT ER - TY - JOUR AU - Mihalovits, Levente Márk AU - Ferenczy, György AU - Keserű, György Miklós TI - Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors JF - COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL J2 - CSBJ VL - 19 PY - 2021 SP - 4486 EP - 4496 PG - 11 SN - 2001-0370 DO - 10.1016/j.csbj.2021.08.008 UR - https://m2.mtmt.hu/api/publication/32298742 ID - 32298742 AB - The ubiquitin-proteasome system is responsible for the degradation of proteins and plays a critical role in key cellular processes. While the constitutive proteasome (cPS) is expressed in all eukaryotic cells, the immunoproteasome (iPS) is primarily induced during disease processes, and its inhibition is beneficial in the treatment of cancer, autoimmune disorders and neurodegenerative diseases. Oxathiazolones were reported to selectively inhibit iPS over cPS, and the inhibitory activity of several oxathiazolones against iPS was experimentally determined. However, the detailed mechanism of the chemical reaction leading to irreversible iPS inhibition and the key selectivity drivers are unknown, and separate characterization of the noncovalent and covalent inhibition steps is not available for several compounds. Here, we investigate the chemical reaction between oxathiazolones and the Thr1 residue of iPS by quantum mechanics/ molecular mechanics (QM/MM) simulations to establish a plausible reaction mechanism and to determine the rate-determining step of covalent complex formation. The modelled binding mode and reaction mechanism are in line with the selective inhibition of iPS versus cPS by oxathiazolones. The k(inact )value of several ligands was estimated by constructing the potential of mean force of the rate-determining step by QM/MM simulations coupled with umbrella sampling. The equilibrium constant K-i of the noncovalent complex formation was evaluated by classical force field-based thermodynamic integration. The calculated K-i and kinact values made it possible to analyse the contribution of the noncovalent and covalent steps to the overall inhibitory activity. Compounds with similar intrinsic reactivities exhibit varying selectivities for iPS versus cPS owing to subtle differences in the binding modes that slightly affect K-i, the noncovalent affinity, and importantly alter k(inact), the covalent reactivity of the bound compounds. A detailed understanding of the inhibitory mechanism of oxathiazolones is useful in designing iPS selective inhibitors with improved drug-like properties. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. 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 - Mihalovits, Levente Márk AU - Ferenczy, György AU - Keserű, György Miklós TI - Catalytic Mechanism and Covalent Inhibition of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA): Implications to the Design of Novel Antibacterials JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING J2 - J CHEM INF MODEL VL - 59 PY - 2019 IS - 12 SP - 5161 EP - 5173 PG - 13 SN - 1549-9596 DO - 10.1021/acs.jcim.9b00691 UR - https://m2.mtmt.hu/api/publication/30939230 ID - 30939230 LA - English DB - MTMT ER -