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In silico discovery and optimisation of a novel structural class of Hsp90 C-terminal domain inhibitors
ID Zajec, Živa (Avtor), ID Dernovšek, Jaka (Avtor), ID Gobec, Martina (Avtor), ID Tomašič, Tihomir (Avtor)

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Izvleček
Hsp90 is a promising target for the development of novel agents for cancer treatment. The N-terminal Hsp90 inhibitors have several therapeutic limitations, the most important of which is the induction of heat shock response, which can be circumvented by targeting the allosteric binding site on the C-terminal domain (CTD) of Hsp90. In the absence of an Hsp90—CTD inhibitor co-crystal structure, the use of structure-based design approaches for the Hsp90 CTD is difficult and the structural diversity of Hsp90 CTD inhibitors is limited. In this study, we describe the discovery of a novel structural class of Hsp90 CTD inhibitors. A structure-based virtual screening was performed by docking a library of diverse compounds to the Hsp90β CTD binding site. Three selected virtual hits were tested in the MCF-7 breast cancer cell line, with compound TVS-23 showing antiproliferative activity with an IC50 value of 26.4 ± 1.1 µM. We report here the optimisation, synthesis and biological evaluation of TVS-23 analogues. Several analogues showed significantly enhanced antiproliferative activities in MCF-7 breast cancer and SK-N-MC Ewing sarcoma cell lines, with 7l being the most potent (IC50 = 1.4 ± 0.4 µM MCF-7; IC50 = 2.8 ± 0.4 µM SK-N-MC). The results of this study highlight the use of virtual screening to expand the structural diversity of Hsp90 CTD inhibitors and provide new starting points for further development.

Jezik:Angleški jezik
Ključne besede:allosteric, cancer, heat shock, Hsp90, inhibitor, virtual screening
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Datum objave:24.06.2022
Leto izida:2022
Št. strani:23 str.
Številčenje:Vol. 12, iss. 7, art 884
PID:20.500.12556/RUL-137880-7c8e690d-baec-291e-1804-da01785a1b6b Povezava se odpre v novem oknu
UDK:615.4:54:616-006
ISSN pri članku:2218-273X
DOI:10.3390/biom12070884 Povezava se odpre v novem oknu
COBISS.SI-ID:113870339 Povezava se odpre v novem oknu
Datum objave v RUL:05.07.2022
Število ogledov:569
Število prenosov:84
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
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Gradivo je del revije

Naslov:Biomolecules
Skrajšan naslov:Biomolecules
Založnik:MDPI
ISSN:2218-273X
COBISS.SI-ID:519952921 Povezava se odpre v novem oknu

Licence

Licenca:CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
Povezava:http://creativecommons.org/licenses/by/4.0/deed.sl
Opis:To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
Začetek licenciranja:05.07.2022

Sekundarni jezik

Jezik:Slovenski jezik
Ključne besede:alosterični, toplotni šok, Hsp90, inhibitorji, virtualno rešetanje

Projekti

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:N1-0208
Naslov:Avtomorfizmi in izomorfizmi končnih grafov

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:J1-1717
Naslov:Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem

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