@{MTMT:34535308,
	title = {Free Energy Calculations in Covalent Drug Design},
	url = {https://m2.mtmt.hu/api/publication/34535308},
	author = {Mihalovits, Levente Márk and Ferenczy, György and Keserű, György Miklós},
	booktitle = {Computational Drug Discovery},
	doi = {10.1002/9783527840748.ch23},
	unique-id = {34535308},
	year = {2024},
	pages = {561-578},
	orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Ferenczy, György/0000-0002-5771-4616}
}

@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}
}

@article{MTMT:32298744,
	title = {The role of quantum chemistry in covalent inhibitor design},
	url = {https://m2.mtmt.hu/api/publication/32298744},
	author = {Mihalovits, Levente Márk and Ferenczy, György and Keserű, György Miklós},
	doi = {10.1002/qua.26768},
	journal-iso = {INT J QUANTUM CHEM},
	journal = {INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY},
	volume = {122},
	unique-id = {32298744},
	issn = {0020-7608},
	abstract = {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.},
	keywords = {MOLECULAR MECHANICS; REACTIVITY; quantum mechanics; free energy; Targeted covalent inhibitors; reaction barrier},
	year = {2022},
	eissn = {1097-461X},
	orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Ferenczy, György/0000-0002-5771-4616}
}

@article{MTMT:33543903,
	title = {A kovalens enziminhibíció számításos kémiai jellemzése},
	url = {https://m2.mtmt.hu/api/publication/33543903},
	author = {Mihalovits, Levente Márk and Ferenczy, György and Keserű, György Miklós},
	doi = {10.24100/MKF.2022.03-4.150},
	journal-iso = {MAGY KÉM FOLY KÉM KÖZL},
	journal = {MAGYAR KÉMIAI FOLYÓIRAT - KÉMIAI KÖZLEMÉNYEK (1997-)},
	volume = {128},
	unique-id = {33543903},
	issn = {1418-9933},
	year = {2022},
	eissn = {1418-8600},
	pages = {150-156},
	orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Ferenczy, György/0000-0002-5771-4616}
}

@article{MTMT:32992489,
	title = {Molecular Dynamics Simulations and Diversity Selection by Extended Continuous Similarity Indices},
	url = {https://m2.mtmt.hu/api/publication/32992489},
	author = {Rácz, Anita and Mihalovits, Levente Márk and Bajusz, Dávid and Héberger, Károly and Miranda-Quintana, Ramón Alain},
	doi = {10.1021/acs.jcim.2c00433},
	journal-iso = {J CHEM INF MODEL},
	journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING},
	volume = {62},
	unique-id = {32992489},
	issn = {1549-9596},
	year = {2022},
	eissn = {1549-960X},
	pages = {3415-3425},
	orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Bajusz, Dávid/0000-0003-4277-9481; Miranda-Quintana, Ramón Alain/0000-0003-2121-4449}
}

@article{MTMT:32298742,
	title = {Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors},
	url = {https://m2.mtmt.hu/api/publication/32298742},
	author = {Mihalovits, Levente Márk and Ferenczy, György and Keserű, György Miklós},
	doi = {10.1016/j.csbj.2021.08.008},
	journal-iso = {CSBJ},
	journal = {COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL},
	volume = {19},
	unique-id = {32298742},
	issn = {2001-0370},
	abstract = {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.},
	keywords = {molecular dynamics; free energy calculation; Immunoproteasome; covalent inhibition; Covalent drug discovery; Oxathiazolones; QM/MM potential},
	year = {2021},
	eissn = {2001-0370},
	pages = {4486-4496},
	orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Ferenczy, György/0000-0002-5771-4616}
}

@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:30939230,
	title = {Catalytic Mechanism and Covalent Inhibition of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA): Implications to the Design of Novel Antibacterials},
	url = {https://m2.mtmt.hu/api/publication/30939230},
	author = {Mihalovits, Levente Márk and Ferenczy, György and Keserű, György Miklós},
	doi = {10.1021/acs.jcim.9b00691},
	journal-iso = {J CHEM INF MODEL},
	journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING},
	volume = {59},
	unique-id = {30939230},
	issn = {1549-9596},
	year = {2019},
	eissn = {1549-960X},
	pages = {5161-5173},
	orcid-numbers = {Mihalovits, Levente Márk/0000-0003-1022-3294; Ferenczy, György/0000-0002-5771-4616}
}