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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_SC - Článek v periodiku v databázi SCOPUS

CEP obor

—

OECD FORD obor

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

Projekt

<a href="/cs/project/GA24-12155S" target="_blank" >GA24-12155S: Studium funkce histon deacetylázy 11 napříč říšemi života</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Computers in Biology Medicine

ISSN

0010-4825

e-ISSN

1879-0534

Svazek periodika

196

Číslo periodika v rámci svazku

Part A

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

19

Strana od-do

110695

Kód UT WoS článku

—

EID výsledku v databázi Scopus

2-s2.0-105009621956