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

J 2023

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

MOTLOVA, Lucia; Ivan SNAJDR; Zsofia KUTIL; Erik ANDRIS; Jakub PTACEK et. al.

Základní údaje

Originální název

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

Autoři

Vydání

ACS Chemical Biology, WASHINGTON, AMER CHEMICAL SOC, 2023, 1554-8929

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.500

Kód RIV

RIV/00216224:90127/23:00139195

Organizační jednotka

CIISB II

DOI

https://doi.org/10.1021/acschembio.3c00212

UT WoS

001021443200001

EID Scopus

2-s2.0-85164798151

Klíčová slova anglicky

BASIS-SETS; ENERGY; COSMO; REFINEMENT; ACIDION

Štítky

ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 28. 3. 2025 11:30, Mgr. Eva Dubská

Anotace

V originále

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 the -CF3 or -CHF2 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.

Návaznosti

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

MOTLOVA, Lucia; Ivan SNAJDR; Zsofia KUTIL; Erik ANDRIS; Jakub PTACEK; Adela NOVOTNA; Zora NOVAKOVA; Barbora HAVLINOVA; Werner TUECKMANTEL; Helena DRABEROVA; Pavel MAJER; Mike SCHUTKOWSKI; Alan KOZIKOWSKI; Lubomir RULISEK a Cyril BARINKA. Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6). ACS Chemical Biology. WASHINGTON: AMER CHEMICAL SOC, 2023, roč. 18, č. 7, s. 1594-1610. ISSN 1554-8929. Dostupné z: https://doi.org/10.1021/acschembio.3c00212.

@article{2487225,
   author = {Motlova, Lucia and Snajdr, Ivan and Kutil, Zsofia and Andris, Erik and Ptacek, Jakub and Novotna, Adela and Novakova, Zora and Havlinova, Barbora and Tueckmantel, Werner and Draberova, Helena and Majer, Pavel and Schutkowski, Mike and Kozikowski, Alan and Rulisek, Lubomir and Barinka, Cyril},
   article_location = {WASHINGTON},
   article_number = {7},
   doi = {https://doi.org/10.1021/acschembio.3c00212},
   keywords = {BASIS-SETS; ENERGY; COSMO; REFINEMENT; ACIDION},
   language = {eng},
   issn = {1554-8929},
   journal = {ACS Chemical Biology},
   title = {Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)},
   url = {https://pubs.acs.org/doi/10.1021/acschembio.3c00212},
   volume = {18},
   year = {2023}
}

TY  - JOUR
ID  - 2487225
AU  - Motlova, Lucia - Snajdr, Ivan - Kutil, Zsofia - Andris, Erik - Ptacek, Jakub - Novotna, Adela - Novakova, Zora - Havlinova, Barbora - Tueckmantel, Werner - Draberova, Helena - Majer, Pavel - Schutkowski, Mike - Kozikowski, Alan - Rulisek, Lubomir - Barinka, Cyril
PY  - 2023
TI  - Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)
JF  - ACS Chemical Biology
VL  - 18
IS  - 7
SP  - 1594-1610
EP  - 1594-1610
PB  - AMER CHEMICAL SOC
SN  - 15548929
KW  - BASIS-SETS
KW  - ENERGY
KW  - COSMO
KW  - REFINEMENT
KW  - ACIDION
UR  - https://pubs.acs.org/doi/10.1021/acschembio.3c00212
N2  - 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 the -CF3 or -CHF2 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.
ER  -

MOTLOVA, Lucia; Ivan SNAJDR; Zsofia KUTIL; Erik ANDRIS; Jakub PTACEK; Adela NOVOTNA; Zora NOVAKOVA; Barbora HAVLINOVA; Werner TUECKMANTEL; Helena DRABEROVA; Pavel MAJER; Mike SCHUTKOWSKI; Alan KOZIKOWSKI; Lubomir RULISEK a Cyril BARINKA. Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6). \textit{ACS Chemical Biology}. WASHINGTON: AMER CHEMICAL SOC, 2023, roč.~18, č.~7, s.~1594-1610. ISSN~1554-8929. Dostupné z: https://doi.org/10.1021/acschembio.3c00212.

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