{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:02:39Z","timestamp":1785420159548,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020599","name":"Al Ain University","doi-asserted-by":"crossref","award":["Ph2021-2-904, Ph2023-4-102 and Ph2024-5-101"],"award-info":[{"award-number":["Ph2021-2-904, Ph2023-4-102 and Ph2024-5-101"]}],"id":[{"id":"10.13039\/100020599","id-type":"DOI","asserted-by":"crossref"}]},{"award":["Ph2021-2-904, Ph2023-4-102 and Ph2024-5-101"],"award-info":[{"award-number":["Ph2021-2-904, Ph2023-4-102 and Ph2024-5-101"]}],"id":[{"id":"https:\/\/ror.org\/023abrt21","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Pharmacological inhibition of the nucleoside transporter hENT1 is a promising therapeutic target across a range of diseases, including cardiovascular disorders, neurodegenerative conditions, and cancer. However, current inhibitors lack drug-like properties, necessitating the development of new inhibitors with improved pharmacological profiles. We employed a dual-pharmacophore virtual screening protocol to identify putative hENT1 inhibitors from a library of over 2 million compounds, followed by structure-based molecular docking. To validate the inhibition effect of the lead compounds, we established a functional assay using gemcitabine (GEM)-induced cytotoxicity as a readout of hENT transport activity using eight cancer cell lines. H292 was the optimal cancer cell line for the validation assay based on its high GEM sensitivity (IC50 = 28 nM) and the concentration-dependent cytotoxicity inhibition of the reference inhibitor NBTI, a hENT1 inhibitor. Of the 19 candidate compounds, two leads (compounds 2 and 3) demonstrated potency comparable to NBTI, increasing GEM IC50 values by 2.2- and 2.9-fold at 5 \u00b5M, respectively. Both compounds were non-cytotoxic to normal fibroblasts, exhibited favorable ADME properties, displayed superior docking scores of \u221212.63 and \u221212.49 kcal\/mol compared to NBTI (\u22129.06 kcal\/mol), and displayed a novel vertical binding orientation within the hENT1 binding pocket distinct from NBTI\u2019s horizontal mode. This study established a validated non-radioactive, gemcitabine-based functional assay for hENT inhibitor discovery and identified two putative inhibitors with therapeutic potential for cancer chemosensitization, pain management, and cardio- and neuroprotection. The non-radioactive functional assay overcomes the limitations of traditional radiolabeled methods, enabling scalable, broader screening applications.<\/jats:p>","DOI":"10.3390\/molecules31081293","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T15:56:56Z","timestamp":1776268616000},"page":"1293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Putative Equilibrative Nucleoside Transporter Inhibitors Through Dual-Pharmacophore Virtual Screening and Validation in a Gemcitabine-Based Cell Assay"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6480-4292","authenticated-orcid":false,"given":"Sedra","family":"Kremesh","sequence":"first","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5988-7783","authenticated-orcid":false,"given":"Azza","family":"Ramadan","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7221-2745","authenticated-orcid":false,"given":"Sedq Ahmad","family":"Moutraji","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9984-243X","authenticated-orcid":false,"given":"Shaima","family":"Hasan","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4249-5200","authenticated-orcid":false,"given":"Radwa E.","family":"Mahgoub","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imogen R.","family":"Coe","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Engineering, Science and Technology (iBEST), Toronto, ON M5B 1T8, Canada"},{"name":"Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Sammani","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama","family":"Abuamer","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor","family":"Atatreh","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2240-8037","authenticated-orcid":false,"given":"Mohammad A.","family":"Ghattas","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/15257770.2016.1210805","article-title":"Equilibrative Nucleoside Transporters\u2014A Review","volume":"36","author":"Hays","year":"2017","journal-title":"Nucleosides Nucleotides Nucleic 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