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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 [Elektronski vir]Herlah, Barbara, farmacevtka ...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.Source: Computational and Structural Biotechnology Journal [Elektronski vir]. - ISSN 2001-0370 (Vol. , 2024,
) Type of material - e-article ; adult, seriousPublish date - 2024Language - englishCOBISS.SI-ID - 200950531
Author
Herlah, Barbara, farmacevtka |
Goričan, Tjaša |
Strašek Benedik, Nika |
Golič Grdadolnik, Simona |
Sosič, Izidor |
Perdih, Andrej, farmacevt
Topics
Rak (medicina) |
Farmacevtska kemija |
molecular design |
molecular simulations |
deep learning |
human DNA |
topoisomerase IIα |
catalytic inhibitors |
anticancer agents |
molekularna zasnova |
molekularne simulacije |
globoko učenje |
človeška DNA |
topoizomeraza IIα |
katalitični inhibitorji |
sredstva proti raku
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Herlah, Barbara, farmacevtka | 54668 |
Goričan, Tjaša | 39078 |
Strašek Benedik, Nika | 52378 |
Golič Grdadolnik, Simona | 08329 |
Sosič, Izidor | 30816 |
Perdih, Andrej, farmacevt | 25493 |
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