In silico screening of a designed focused chemical space identifies novel alkyl hydrazides as potent HDAC11 inhibitors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F25%3A00647818" target="_blank" >RIV/86652036:_____/25:00647818 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0010482525010467" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0010482525010467</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.compbiomed.2025.110695" target="_blank" >10.1016/j.compbiomed.2025.110695</a>

Result language

angličtina

Original language name

In silico screening of a designed focused chemical space identifies novel alkyl hydrazides as potent HDAC11 inhibitors

Original language description

The therapeutic potential of HDAC inhibitors containing a hydroxamic acid moiety as a zinc-binding group (ZBG) is limited in clinical use due to their potential mutagenicity. In addition, hydroxamic acids often exhibit off-target effects that can lead to undesirable toxicity. Therefore, the development of HDAC inhibitors with alternative ZBGs has proven to be a promising approach to overcome these drawbacks. HDAC inhibitors carrying alkyl hydrazide as ZBG have recently been published as selective inhibitors for different HDAC subtypes. In the present study, a ligand-based virtual screening workflow, employing a classification categorical model, was developed and applied for a designed targeted chemical space. The two most promising hits from the virtual screening were synthesized and evaluated by in vitro enzyme inhibition assays. Both hits showed strong inhibition of HDAC11 with IC<inf>50</inf> values in the nanomolar range. In addition, the compounds showed good selectivity towards HDAC11 at a concentration of 1 μM, only HDAC8 was also significantly inhibited among all tested subtypes. Finally, the binding mode of the selected candidates was investigated by docking against different HDACs, followed by molecular dynamics simulations and metadynamics studies to provide insights for further chemical optimization.

Czech name

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Czech description

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Type

J_SC - Article in a specialist periodical, which is included in the SCOPUS database

CEP classification

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OECD FORD branch

10602 - Biology (theoretical, mathematical, thermal, cryobiology, biological rhythm), Evolutionary biology

Project

<a href="/en/project/GA24-12155S" target="_blank" >GA24-12155S: Elucidating functions of histone deacetylase 11 throughout the kingdoms of life</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

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

Name of the periodical

Computers in Biology Medicine

ISSN

0010-4825

e-ISSN

1879-0534

Volume of the periodical

196

Issue of the periodical within the volume

Part A

Country of publishing house

GB - UNITED KINGDOM

Number of pages

19

Pages from-to

110695

UT code for WoS article

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EID of the result in the Scopus database

2-s2.0-105009621956