Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00574532" target="_blank" >RIV/61388963:_____/23:00574532 - isvavai.cz</a>

Alternative codes found

RIV/86652036:_____/23:00574532

Result on the web

<a href="https://pubs.acs.org/doi/10.1021/acschembio.3c00212" target="_blank" >https://pubs.acs.org/doi/10.1021/acschembio.3c00212</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acschembio.3c00212" target="_blank" >10.1021/acschembio.3c00212</a>

Result language

angličtina

Original language name

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

ACS Chemical Biology

ISSN

1554-8929

e-ISSN

1554-8937

Volume of the periodical

18

Issue of the periodical within the volume

7

Country of publishing house

US - UNITED STATES

Number of pages

17

Pages from-to

1594-1610

UT code for WoS article

001021443200001

EID of the result in the Scopus database

2-s2.0-85164798151