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A large number of chemically dissimilar drugs are transported, and despite extensive studies, the molecular determinants of substrate specificity are still not well understood. In this work, we explore the role of polar and non-polar interactions on the interaction of a homologous series of fluorescent amphiphiles with the efflux transporter P-glycoprotein. The interaction of the amphiphiles with P-glycoprotein is evaluated through effects on ATPase activity, efficiency in inhibition of [125I]-IAAP binding, and partition to the whole native membranes containing the transporter. The results were complemented with partition to model membranes with a representative lipid composition, and details on the interactions established were obtained from MD simulations. We show that when the total concentration of amphiphile is considered, the binding parameters obtained are apparent and do not reflect the affinity for P\u2013gp. A new formalism is proposed that includes sequestration of the amphiphiles in the lipid bilayer and the possible binding of several molecules in P\u2013gp\u2019s substrate-binding pocket. The intrinsic binding affinity thus obtained is essentially independent of amphiphile hydrophobicity, highlighting the importance of polar interactions. An increase in the lipophilicity and amphiphilicity led to a more efficient association with the lipid bilayer, which maintains the non-polar groups of the amphiphiles in the bilayer, while the polar groups interact with P\u2013gp\u2019s binding pocket. The presence of several amphiphiles in this orientation is proposed as a mechanism for inhibition of P-pg function.<\/jats:p>","DOI":"10.3390\/pharmaceutics15010174","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T01:42:44Z","timestamp":1672796564000},"page":"174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Interaction of a Homologous Series of Amphiphiles with P-glycoprotein in a Membrane Environment\u2014Contributions of Polar and Non-Polar Interactions"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-9905","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Moreno","sequence":"first","affiliation":[{"name":"Coimbra Chemistry Center-Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6935-4307","authenticated-orcid":false,"given":"Hugo A. L.","family":"Filipe","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Center-Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"CPIRN-IPG\u2014Center of Potential and Innovation of Natural Resources, Polytechnic of Guarda, 6300-559 Guarda, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1848-9038","authenticated-orcid":false,"given":"Susana V. P.","family":"Cunha","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Center-Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2075-3697","authenticated-orcid":false,"given":"Cristiana V.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Center-Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"given":"Patr\u00edcia A. T.","family":"Martins","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Center-Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8817-9054","authenticated-orcid":false,"given":"Biebele","family":"Abel","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, CCR, National Cancer Institute, NIH, Bethesda, MD 20892, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Uniformed Services University of the Health Science, Bethesda, MD 20817, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1051-2312","authenticated-orcid":false,"given":"Lu\u00eds M. 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