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Identification of a novel structural class of H▫$_v$▫1 inhibitors by structure-based virtual screeningPiga, Martina ...The human voltage-gated proton channel, hHv1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression ... of Hv1 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 hHv1 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 Hv1 channel. Twenty selected virtual screening hits were tested on Chinese hamster ovary (CHO) cells transiently expressing hHv1, with compound 13 showing strong block of the proton current with an IC50 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 hHv1 inhibitors was investigated in the cell lines MDA-MB-231 and THP-1, where compound 13 inhibited growth with an IC50 value of 9.0 and 8.1 μM, respectively. The identification of a new structural class of Hv1 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 Hv1 inhibitors in various pathological conditions and in cancer therapy.Vir: Journal of chemical information and modeling [Elektronski vir]. - ISSN 1549-960X (Vol. 64, iss. 12, 2024, str. 4850-4862)Vrsta gradiva - e-članek ; neleposlovje za odrasleLeto - 2024Jezik - angleškiCOBISS.SI-ID - 199158019
Avtor
Piga, Martina |
Varga, Zoltán, medicinec |
Fehér, Ádám |
Papp, Ferenc, medicinec |
Korpos Pintye-Gyuri, Eva |
Bangera, Kavya C. |
Frlan, Rok |
Ilaš, Janez |
Dernovšek, Jaka |
Tomašič, Tihomir |
Zidar, Nace
Teme
Rak (medicina) |
cancer |
cells |
inhibition |
inhibitors |
screening assays |
celice |
inhibicija |
inhibitorji |
presejalni testi
Vnos na polico
Trajna povezava
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Faktor vpliva
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Piga, Martina | 55894 |
Varga, Zoltán, medicinec | |
Fehér, Ádám | |
Papp, Ferenc, medicinec | |
Korpos Pintye-Gyuri, Eva | |
Bangera, Kavya C. | |
Frlan, Rok | 26512 |
Ilaš, Janez | 24400 |
Dernovšek, Jaka | 54784 |
Tomašič, Tihomir | 28334 |
Zidar, Nace | 28905 |
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