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Search for the new class of anticancer drugs on the basis of yb-1 cold shock domain inhibitorsтезисы доклада Тезисы
- Авторы: Ilin I., Moiseeva N., Shikhaliev K., Tarasov A., Mordovkina D., Grigoreva E., Ovchinnikov L., Guens G., Sulimov V.
- Сборник: ХХI Mendeleev Congress on General and Applied Chemistry. Book of abstracts in 6 volumes
- Серия: Book 6. Satellite symposia
- Том: 6
- Тезисы
- Год издания: 2019
- Место издания: Saint Petersburg
- Первая страница: 68
- Последняя страница: 68
- Аннотация: Y box binding protein-1 (YB-1) is a cold shock domain (CSD) containing protein. Functionally, YB-1 is DNA and RNA binding protein involved in regulation of several proteins contributing to oncogenesis, metastasis and drug resistance of cancer cells. Inhibition of YB-1 decreases the cell proliferation and migration, and increases sensitivity of cancer cells to drugs. Our work is aimed to search for inhibitors of YB-1 activity by molecular modeling. Binding a small molecule to a site on the surface of CSD of YB-1 near Ser102 is shown to hinder activation of YB-1 and its nuclear translocation, the key process driving malignization. We target the same region and apply ensemble docking to address issues associated with flxibility of the site. Prior to docking, protein conformations retrieved from the NMR-resolved structure of CSD are optimized by using the semiempirical quantum-chemical PM7 method with the COSMO solvent model and assessed by docking of two known YB-1 inhibitors. Four working models are selected for ensemble docking. Virtual screening of Voronezh State University base consisting of around 14000 compounds is then performed by using the SOL docking program. Tens of top compounds ranked by the SOL score are subjected to re-docking with a new approach combining a force fild and the PM7 method with COSMO solvent in order to calculate binding energy more accurately and 13 candidates for experimental testing are selected relying upon their binding energies, poses and scores. Of these, two compounds, VGY0018645 and VGY0018615, have discernible cytotoxic effct on HCT-116 cells in the MTT assay. Both compounds contain octahydroquinazolinone fused with triazole as a scaffld. VGY0018615 shows the most potent effct on HCT-116 cells (human colon cancer cell line) with the IC50 being 5 μM. Moreover, VGY0018615 possesses a selective cytotoxicity and does not inhibit viability of human embryonic firoblasts.
- Добавил в систему: Ильин Иван Сергеевич