Identification of a novel structural class of H$_v$1 inhibitors by structure-based virtual screeningPiga, Martina (Avtor) Varga, Zoltán (Avtor) Fehér, Ádám (Avtor) Papp, Ferenc (Avtor) Korpos Pintye-Gyuri, Eva (Avtor) Bangera, Kavya C. (Avtor) Frlan, Rok (Avtor) Ilaš, Janez (Avtor) Dernovšek, Jaka (Avtor) Tomašič, Tihomir (Avtor) Zidar, Nace (Avtor) cancercellsinhibitioninhibitorsscreening assaysThe human voltage-gated proton channel, hH$_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.20242024-06-26 14:34:17Članek v reviji158987UDK: 616-07:616-006ISSN pri članku: 1549-960XDOI: 10.1021/acs.jcim.4c00240COBISS_ID: 199158019sl