20.500.12556/RUL-158987 Identification of a novel structural class of H$_v$1 inhibitors by structure-based virtual screening The human voltage-gated proton channel, hH$_v$1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of H$_v$1 has been shown to promote tumor formation by highly metastatic cancer cells, and has been associated with neuroinflammatory diseases, immune response disorders and infertility, suggesting a potential use of hH$_v$1 inhibitors in numerous therapeutic areas. To identify compounds targeting this channel, we performed a structure-based virtual screening on an open structure of the human H$_v$1 channel. Twenty selected virtual screening hits were tested on Chinese hamster ovary (CHO) cells transiently expressing hH$_v$1, with compound 13 showing strong block of the proton current with an IC$_{50}$ value of 8.5 μM. Biological evaluation of twenty-three additional analogs of 13 led to the discovery of six other compounds that blocked the proton current by more than 50% at 50 μM concentration. This allowed for an investigation of structure–activity relationships. The antiproliferative activity of the selected promising hH$_v$1 inhibitors was investigated in the cell lines MDA-MB-231 and THP-1, where compound 13 inhibited growth with an IC$_{50}$ value of 9.0 and 8.1 μM, respectively. The identification of a new structural class of H$_v$1 inhibitors contributes to our understanding of the structural requirements for inhibition of this ion channel and opens up the possibility of investigating the role of H$_v$1 inhibitors in various pathological conditions and in cancer therapy. cancer cells inhibition inhibitors screening assays rak celice inhibicija inhibitorji presejalni testi true false true Angleški jezik Slovenski jezik Članek v reviji 2024-06-26 14:34:17 2024-06-26 14:34:23 2024-07-07 03:29:34 0000-00-00 00:00:00 2024 0 0 Str. 4850–4862 iss. 12 Vol. 64 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-07:616-006 1549-960X 10.1021/acs.jcim.4c00240 199158019 piga-et-al-2024-identification-of-a-novel-structural-class-of-hv1-inhibitors-by-structure-based-virtual-screening.pdf piga-et-al-2024-identification-of-a-novel-structural-class-of-hv1-inhibitors-by-structure-based-virtual-screening.pdf 1 1150CAEC97F2B63CC10C56268F6F2817 a03ccaa170bbd712a7d228e284addfbf82d4522cdb90a2cc3b6e08718ee9732e b9fe512d-33b8-11ef-8fa5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=186734 https://pubs.acs.org/doi/10.1021/acs.jcim.4c00240 1 6b986120-33b8-11ef-8fa5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=186733 Fakulteta za farmacijo 0 0 0