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Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)
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SYSNO ASEP 0574532 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6) Author(s) Motlová, Lucia (BTO-N) ORCID
Šnajdr, Ivan (UOCHB-X) ORCID
Kutil, Zsofia (BTO-N) RID, ORCID
Andris, Erik (UOCHB-X) ORCID
Ptáček, Jakub (BTO-N) RID
Novotná, Adéla (UOCHB-X) ORCID
Nováková, Zora (BTO-N) ORCID, RID
Havlínová, Barbora (BTO-N)
Tueckmantel, W. (US)
Dráberová, Helena (BTO-N)
Majer, Pavel (UOCHB-X)
Schutkowski, M. (DE)
Kozikowski, A. (US)
Rulíšek, Lubomír (UOCHB-X) RID, ORCID
Bařinka, Cyril (BTO-N) RID, ORCIDNumber of authors 15 Source Title ACS Chemical Biology. - : American Chemical Society - ISSN 1554-8929
Roč. 18, č. 7 (2023), s. 1594-1610Number of pages 17 s. Language eng - English Country US - United States Keywords BASIS-SETS ; COSMO ; ENERGY ; REFINEMENT Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects GA21-31806S GA ČR - Czech Science Foundation (CSF) GA23-05940S GA ČR - Czech Science Foundation (CSF) LUAUS23247 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure CIISB III - 90242 - Masarykova univerzita / Středoevropský technologický institut
EATRIS-CZ IV - 90253 - Univerzita Palackého v Olomouci / Lékařská fakultaMethod of publishing Open access Institutional support BTO-N - RVO:86652036 ; UOCHB-X - RVO:61388963 UT WOS 001021443200001 EID SCOPUS 85164798151 DOI 10.1021/acschembio.3c00212 Annotation Histone deacetylase (HDAC) inhibitors used in the clinictypicallycontain a hydroxamate zinc-binding group (ZBG). However, more recentwork has shown that the use of alternative ZBGs, and, in particular,the heterocyclic oxadiazoles, can confer higher isoenzyme selectivityand more favorable ADMET profiles. Herein, we report on the synthesisand biochemical, crystallographic, and computational characterizationof a series of oxadiazole-based inhibitors selectively targeting theHDAC6 isoform. Surprisingly, but in line with a very recent findingreported in the literature, a crystal structure of the HDAC6/inhibitorcomplex revealed that hydrolysis of the oxadiazole ring transformsthe parent oxadiazole into an acylhydrazide through a sequence oftwo hydrolytic steps. An identical cleavage pattern was also observedboth in vitro using the purified HDAC6 enzyme aswell as in cellular systems. By employing advanced quantum and molecularmechanics (QM/MM) and QM calculations, we elucidated the mechanisticdetails of the two hydrolytic steps to obtain a comprehensive mechanisticview of the double hydrolysis of the oxadiazole ring. This was achievedby fully characterizing the reaction coordinate, including identificationof the structures of all intermediates and transition states, togetherwith calculations of their respective activation (free) energies.In addition, we ruled out several (intuitively) competing pathways.The computed data (& UDelta,G (& DDAG) & AP,21 kcal & BULL,mol(-1) for the rate-determining stepof the overall dual hydrolysis) are in very good agreement with theexperimentally determined rate constants, which a posteriori supports the proposed reaction mechanism. We also clearly (and quantitatively)explain the role of theCF3 orCHF2 substituent on the oxadiazole ring, which is a prerequisitefor hydrolysis to occur. Overall, our data provide compelling evidencethat the oxadiazole warheads can be efficiently transformed withinthe active sites of target metallohydrolases to afford reaction productspossessing distinct selectivity and inhibition profiles. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2024 Electronic address https://pubs.acs.org/doi/10.1021/acschembio.3c00212
Number of the records: 1