Utilization of an optimized AlphaFold protein model for structure-based design of a selective HDAC11 inhibitor with anti-neuroblastoma activity

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F24%3A00617017" target="_blank" >RIV/86652036:_____/24:00617017 - isvavai.cz</a>
Result on the web
<a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400486" target="_blank" >https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400486</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ardp.202400486" target="_blank" >10.1002/ardp.202400486</a>

Result language
angličtina
Original language name
Utilization of an optimized AlphaFold protein model for structure-based design of a selective HDAC11 inhibitor with anti-neuroblastoma activity
Original language description
AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 mu M on neuroblastoma cells.
Czech name
—
Czech description
—

Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy

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
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Similar results(10)