Identification of a novel structural class of H$_v$1 inhibitors by structure-based virtual screening

Piga, Martina (author), Varga, Zoltán (author), Fehér, Ádám (author), Papp, Ferenc (author), Korpos Pintye-Gyuri, Eva (author), Bangera, Kavya C. (author), Frlan, Rok (author), Ilaš, Janez (author), Dernovšek, Jaka (author), Tomašič, Tihomir (author), Zidar, Nace (author)

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.

• Language: English
• Keywords: cancer, cells, inhibition, inhibitors, screening assays
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 4850–4862
• Numbering: Vol. 64, iss. 12
• PID: 20.500.12556/RUL-158987
• UDC: 616-07:616-006
• ISSN on article: 1549-960X
• DOI: 10.1021/acs.jcim.4c00240
• COBISS.SI-ID: 199158019
• Publication date in RUL: 26.06.2024

Record is a part of a journal

• Title: Journal of chemical information and modeling
• Publisher: Amrican Chemical Society
• ISSN: 1549-960X
• COBISS.SI-ID: 3037204

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: rak, celice, inhibicija, inhibitorji, presejalni testi