| High-affinity small molecule-phospholipid complex formation: binding of siramesine to phosphatidic acid. | |
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MedLine Citation:
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PMID: 18767848 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Siramesine (SRM) is a sigma-2 receptor agonist which has been recently shown to inhibit growth of cancer cells. Fluorescence spectroscopy experiments revealed two distinct binding sites for this drug in phospholipid membranes. More specifically, acidic phospholipids retain siramesine on the bilayer surface due to a high-affinity interaction, reaching saturation at an apparent 1:1 drug-acidic phospholipid stoichiometry, where after the drug penetrates into the hydrocarbon core of the membrane. This behavior was confirmed using Langmuir films. Of the anionic phospholipids, the highest affinity, comparable to the affinities for the binding of small molecule ligands to proteins, was measured for phosphatidic acid (PA, mole fraction of X(PA) = 0.2 in phosphatidylcholine vesicles), yielding a molecular partition coefficient of 240 +/- 80 x 10(6). An MD simulation on the siramesine:PA interaction was in agreement with the above data. Taking into account the key role of PA as a signaling molecule promoting cell growth our results suggest a new paradigm for the development of anticancer drugs, viz. design of small molecules specifically scavenging phospholipids involved in the signaling cascades controlling cell behavior. |
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Authors:
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Mikko J Parry; Juha-Matti I Alakoskela; Himanshu Khandelia; Subramanian Arun Kumar; Marja Jäättelä; Ajay K Mahalka; Paavo K J Kinnunen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-09-04 |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 130 ISSN: 1520-5126 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-09-25 Completed Date: 2008-12-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 12953-60 Citation Subset: IM |
Affiliation:
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Helsinki Biophysics & Biomembrane Group, Institute of Biomedicine, University of Helsinki, Finland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Calorimetry, Differential Scanning Computer Simulation Indoles / chemistry*, metabolism Kinetics Lipid Bilayers / chemistry Liposomes / chemistry Phosphatidic Acids / chemistry*, metabolism Phospholipids / chemistry*, metabolism Second Messenger Systems Spectrometry, Fluorescence Spiro Compounds / chemistry*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Indoles; 0/Lipid Bilayers; 0/Liposomes; 0/Lu 28-179; 0/Phosphatidic Acids; 0/Phospholipids; 0/Spiro Compounds |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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