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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
(
Avtor
),
ID
Goričan, Tjaša
(
Avtor
),
ID
Strašek Benedik, Nika
(
Avtor
),
ID
Golič Grdadolnik, Simona
(
Avtor
),
ID
Sosič, Izidor
(
Avtor
),
ID
Perdih, Andrej
(
Avtor
)
PDF - Predstavitvena datoteka,
prenos
(10,65 MB)
MD5: C7B05950999F6F152304245830C749CD
URL - Izvorni URL, za dostop obiščite
https://www.sciencedirect.com/science/article/pii/S2001037024002344
Galerija slik
Izvleček
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.
Jezik:
Angleški jezik
Ključne besede:
molecular design
,
molecular simulations
,
deep learning
,
human DNA
,
topoisomerase IIα
,
catalytic inhibitors
,
anticancer agents
Vrsta gradiva:
Članek v reviji
Tipologija:
1.01 - Izvirni znanstveni članek
Organizacija:
FFA - Fakulteta za farmacijo
Status publikacije:
Objavljeno
Različica publikacije:
Objavljena publikacija
Leto izida:
2024
Št. strani:
str. 2995-3018
Številčenje:
Vol. 23
PID:
20.500.12556/RUL-160545
UDK:
615.4:54:616-006
ISSN pri članku:
2001-0370
DOI:
10.1016/j.csbj.2024.06.037
COBISS.SI-ID:
200950531
Datum objave v RUL:
30.08.2024
Število ogledov:
75
Število prenosov:
33
Metapodatki:
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Objavi na:
Gradivo je del revije
Naslov:
Computational and Structural Biotechnology Journal
Založnik:
Chalmers University of Technology
ISSN:
2001-0370
COBISS.SI-ID:
5068826
Licence
Licenca:
CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
Povezava:
http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
Opis:
Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.
Sekundarni jezik
Jezik:
Slovenski jezik
Ključne besede:
molekularna zasnova
,
molekularne simulacije
,
globoko učenje
,
človeška DNA
,
topoizomeraza IIα
,
katalitični inhibitorji
,
sredstva proti raku
,
rak (medicina)
,
farmacevtska kemija
Projekti
Financer:
ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
Številka projekta:
J1-4402
Naslov:
Dinamični model molekulskega stroja DNA topoizomeraze tipa II in razvoj katalitičnih inhibitorjev
Financer:
ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
Številka projekta:
J1-4400
Naslov:
Vrednotenje prehodnih stanj proteinov
Financer:
ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
Številka projekta:
P1-0012
Naslov:
Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin
Financer:
ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
Številka projekta:
P1-0010
Naslov:
Folding in dinamika biomolekularnih sistemov
Financer:
ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
Številka projekta:
P1-0208
Naslov:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Financer:
Drugi - Drug financer ali več financerjev
Program financ.:
Young research program
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