{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:54:42Z","timestamp":1781848482550,"version":"3.54.5"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    OCT1 is a hepatic membrane uptake transporter of clinical importance in drug metabolism and pharmacokinetics. OCT1 exhibits broad substrate specificity, mediating uptake of diverse compounds, including the neurotransmitter serotonin and the antidiabetic drug metformin. Numerous compounds have been reported as OCT1 substrates using\n                    <jats:italic>in vitro<\/jats:italic>\n                    model cell lines overexpressing the transporter and computational prediction approaches, often benchmarked against the prototypical substrate tetraethylammonium. The reported substrate affinities span a wide kinetic range, with\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    values from 0.48\u00a0\u00b5M for prostaglandin F2\u03b1 and prostaglandin E2 to 33,900\u00a0\u00b5M for trimethylamine N-oxide, highlighting the potential for clinically relevant drug\u2013drug competition during cellular uptake. In this study, we establish an integrated framework to evaluate OCT1 substrates using\n                    <jats:italic>in silico<\/jats:italic>\n                    docking and molecular dynamics simulations, complemented by\n                    <jats:italic>in vitro<\/jats:italic>\n                    transport assays. The computational analysis concurs with previous\n                    <jats:italic>in vitro<\/jats:italic>\n                    cell line studies that ethidium bromide is a high-affinity substrate for OCT1, and herein, we validated experimentally that OCT1-deficient HEK293 cells showed negligible uptake of the compound. Competitive uptake experiments further demonstrated that metformin significantly inhibits ethidium bromide transport, indicating that under these conditions, metformin could be a high-affinity OCT1 substrate. In addition, our approach revealed for the first time that vitamin K1 potently inhibits OCT1-mediated transport of ethidium bromide in HEK293 cells. The integration of computational modeling with experimental validation provides a robust strategy for identifying and characterizing high-affinity OCT1 ligands and highlights the importance of OCT1 in drug transport, nutrient uptake, and potential drug\u2013drug interactions.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1830280","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:47:21Z","timestamp":1781848041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Applying molecular dynamics simulations to validate OCT1 substrates uncovers vitamin K1 as a high-affinity ligand"],"prefix":"10.3389","volume":"17","author":[{"given":"Elham Omer","family":"Mahgoub","sequence":"first","affiliation":[{"name":"College of Arts and Sciences, Qatar University","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem","family":"Ali","sequence":"additional","affiliation":[{"name":"Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayman","family":"Samara","sequence":"additional","affiliation":[{"name":"Qatar Environment and Energy Research Institute, Hamad Bin Khalifa University","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dindial","family":"Ramotar","sequence":"additional","affiliation":[{"name":"Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"B1","first-page":"1","article-title":"Molecular dynamic simulations and molecular docking as a potential way for designed new inhibitor drug without resistance","volume":"21","author":"Aghajani","year":"2022","journal-title":"Tanaffos"},{"key":"B2","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1002\/med.20067","article-title":"Combining docking and molecular dynamic simulations in drug design","volume":"26","author":"Alonso","year":"2006","journal-title":"Med. 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