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

Piga, 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)

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.

• Jezik: Angleški jezik
• Ključne besede: cancer, cells, inhibition, inhibitors, screening assays
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: Str. 4850–4862
• Številčenje: Vol. 64, iss. 12
• PID: 20.500.12556/RUL-158987
• UDK: 616-07:616-006
• ISSN pri članku: 1549-960X
• DOI: 10.1021/acs.jcim.4c00240
• COBISS.SI-ID: 199158019
• Datum objave v RUL: 26.06.2024

Gradivo je del revije

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

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.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: rak, celice, inhibicija, inhibitorji, presejalni testi