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Simulation- and AI-directed optimization of 4,6-substituted 1,3,5-triazin-2(1H)-ones as inhibitors of human DNA topoisomerase IIα
ID
Herlah, Barbara
(
Author
),
ID
Goričan, Tjaša
(
Author
),
ID
Strašek Benedik, Nika
(
Author
),
ID
Golič Grdadolnik, Simona
(
Author
),
ID
Sosič, Izidor
(
Author
),
ID
Perdih, Andrej
(
Author
)
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https://www.sciencedirect.com/science/article/pii/S2001037024002344
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Abstract
The 4,6-substituted-1,3,5-triazin-2(1H)-ones are promising inhibitors of human DNA topoisomerase IIα. To further develop this chemical class targeting the enzyme´s ATP binding site, the triazin-2(1H)-one substitution position 6 was optimized. Inspired by binding of preclinical substituted 9H-purine derivative, bicyclic substituents were incorporated at position 6 and the utility of this modification was validated by a combination of molecular simulations, dynamic pharmacophores, and free energy calculations. Considering also predictions of Deepfrag, a software developed for structure-based lead optimization based on deep learning, compounds with both bicyclic and monocyclic substitutions were synthesized and investigated for their inhibitory activity. The SAR data showed that the bicyclic substituted compounds exhibited good inhibition of topo IIα, comparable to their mono-substituted counterparts. Further evaluation on a panel of human protein kinases showed selectivity for the inhibition of topo IIα. Mechanistic studies indicated that the compounds acted predominantly as catalytic inhibitors, with some exhibiting topo IIα poison effects at higher concentrations. Integration of STD NMR experiments and molecular simulations, provided insights into the binding model and highlighted the importance of the Asn120 interaction and hydrophobic interactions with substituents at positions 4 and 6. In addition, NCI-60 screening demonstrated cytotoxicity of the compounds with bicyclic substituents and identified sensitive human cancer cell lines, underlining the translational relevance of our findings for further preclinical development of this class of compounds. The study highlights the synergy between simulation and AI-based approaches in efficiently guiding molecular design for drug optimization, which has implications for further preclinical development of this class of compounds.
Language:
English
Keywords:
molecular design
,
molecular simulations
,
deep learning
,
human DNA
,
topoisomerase IIα
,
catalytic inhibitors
,
anticancer agents
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
FFA - Faculty of Pharmacy
Publication status:
Published
Publication version:
Version of Record
Year:
2024
Number of pages:
str. 2995-3018
Numbering:
Vol. 23
PID:
20.500.12556/RUL-160545
UDC:
615.4:54:616-006
ISSN on article:
2001-0370
DOI:
10.1016/j.csbj.2024.06.037
COBISS.SI-ID:
200950531
Publication date in RUL:
30.08.2024
Views:
77
Downloads:
33
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Record is a part of a journal
Title:
Computational and Structural Biotechnology Journal
Publisher:
Chalmers University of Technology
ISSN:
2001-0370
COBISS.SI-ID:
5068826
Licences
License:
CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Link:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Description:
The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Secondary language
Language:
Slovenian
Keywords:
molekularna zasnova
,
molekularne simulacije
,
globoko učenje
,
človeška DNA
,
topoizomeraza IIα
,
katalitični inhibitorji
,
sredstva proti raku
,
rak (medicina)
,
farmacevtska kemija
Projects
Funder:
ARIS - Slovenian Research and Innovation Agency
Project number:
J1-4402
Name:
Dinamični model molekulskega stroja DNA topoizomeraze tipa II in razvoj katalitičnih inhibitorjev
Funder:
ARIS - Slovenian Research and Innovation Agency
Project number:
J1-4400
Name:
Vrednotenje prehodnih stanj proteinov
Funder:
ARIS - Slovenian Research and Innovation Agency
Project number:
P1-0012
Name:
Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin
Funder:
ARIS - Slovenian Research and Innovation Agency
Project number:
P1-0010
Name:
Folding in dinamika biomolekularnih sistemov
Funder:
ARIS - Slovenian Research and Innovation Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
Other - Other funder or multiple funders
Funding programme:
Young research program
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