Characterizing the binding interactions between P‐glycoprotein and eight known cardiovascular transport substrates
The multidrug efflux pump P‐glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on...
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| description | The multidrug efflux pump P‐glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on mouse Pgp. Selected Pgp transport ligands include: Amiodarone, Bepridil, Diltiazem, Dipyridamole, Nicardipine, Nifedipine, Propranolol, and Quinidine. Extensive molecular dynamic equilibration simulations were performed to determine drug docking interactions. Distinct binding sites were not observed, but rather a binding belt was seen with multiple residues playing a role in each studied drug's stable docking. Three key drug–protein interactions were identified: hydrogen bonding, hydrophobic packing, and the formation of a “cage” of aromatic residues around the drug. After drug stabilization, water molecules were observed to leak into the binding belt and condense around the drug. Water influx into the binding domain of Pgp may play a role in catalytic transition and drug expulsion. The cytoplasmic recruitment theory was also tested, and the drugs were observed to interact with conserved loops of residues with a strong affinity. A free energy change of astronomical value is required to recruit the drug from the cytoplasm to the binding belt within the transmembrane domain of Pgp.
e00114 |
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e00114</description><subject>ABC transporters</subject><subject>Binding sites</subject><subject>Cancer therapies</subject><subject>Cardiomyocytes</subject><subject>cardiovascular drug binding</subject><subject>Cytoplasm</subject><subject>Drug resistance</subject><subject>Energy</subject><subject>Glycerol</subject><subject>Glycoproteins</subject><subject>Hypoxia</subject><subject>Ligands</subject><subject>mouse Pgp</subject><subject>Original</subject><subject>Pharmacology</subject><subject>Proteins</subject><subject>P‐glycoprotein</subject><subject>Recruitment</subject><subject>Scholarships & fellowships</subject><issn>2052-1707</issn><issn>2052-1707</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kd9qFDEUh4MottSCTyABb7yZ9uTMv-yNIEvVQsFF9DpkMmd2U2eTMcl0Wa98BJ_RJzFLa62CVznJ-fjOCT_Gngs4EwB4PoUJz4SoHrFjhBoL0UL7-EF9xE5jvAaAzIAo8Sk7wrrFRS3FMUvLjQ7aJAr2m3VrnjbEO-v6Q21dfs49613kHaUdkeOrn99_rMe98VPwiazj2vWc7HqT-Bfnd44bHXrrb3Q086gDT0G7OPmQeJy7mG-J4jP2ZNBjpNO784R9fnvxafm-uPrw7nL55qowdYlVMYCUWteEtQRqBzKmAdNJ0IDlUElhyhq7drEwpq1LWmCPvehkW0vswEgpyhP2-tY7zd2WekMuzx_VFOxWh73y2qq_O85u1NrfqCqPb6TMgld3guC_zhST2tpoaBy1Iz9HJZoGqrJtADL68h_02s_B5e8pRClRYlXhH6EJPsZAw_0yAtQhTXVIU-WkMvri4fL34O_sMlDcAjs70v6_IrX6uMKD8Bcsdqy-</recordid><startdate>201503</startdate><enddate>201503</enddate><creator>Jagodinsky, Justin C.</creator><creator>Akgun, Ugur</creator><general>John Wiley & Sons, Inc</general><general>BlackWell Publishing Ltd</general><scope>24P</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PKEHL</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201503</creationdate><title>Characterizing the binding interactions between P‐glycoprotein and eight known cardiovascular transport substrates</title><author>Jagodinsky, Justin C. ; Akgun, Ugur</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5324-f088aa5e2580e7fecc60cb80a023f481c352b799cc753e92d2d1b87582b0c8813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>ABC transporters</topic><topic>Binding sites</topic><topic>Cancer therapies</topic><topic>Cardiomyocytes</topic><topic>cardiovascular drug binding</topic><topic>Cytoplasm</topic><topic>Drug resistance</topic><topic>Energy</topic><topic>Glycerol</topic><topic>Glycoproteins</topic><topic>Hypoxia</topic><topic>Ligands</topic><topic>mouse Pgp</topic><topic>Original</topic><topic>Pharmacology</topic><topic>Proteins</topic><topic>P‐glycoprotein</topic><topic>Recruitment</topic><topic>Scholarships & fellowships</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jagodinsky, Justin C.</creatorcontrib><creatorcontrib>Akgun, Ugur</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Pharmacology research & perspectives</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jagodinsky, Justin C.</au><au>Akgun, Ugur</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterizing the binding interactions between P‐glycoprotein and eight known cardiovascular transport substrates</atitle><jtitle>Pharmacology research & perspectives</jtitle><addtitle>Pharmacol Res Perspect</addtitle><date>2015-03</date><risdate>2015</risdate><volume>3</volume><issue>2</issue><spage>e00114</spage><epage>n/a</epage><pages>e00114-n/a</pages><issn>2052-1707</issn><eissn>2052-1707</eissn><abstract>The multidrug efflux pump P‐glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on mouse Pgp. Selected Pgp transport ligands include: Amiodarone, Bepridil, Diltiazem, Dipyridamole, Nicardipine, Nifedipine, Propranolol, and Quinidine. Extensive molecular dynamic equilibration simulations were performed to determine drug docking interactions. Distinct binding sites were not observed, but rather a binding belt was seen with multiple residues playing a role in each studied drug's stable docking. Three key drug–protein interactions were identified: hydrogen bonding, hydrophobic packing, and the formation of a “cage” of aromatic residues around the drug. After drug stabilization, water molecules were observed to leak into the binding belt and condense around the drug. Water influx into the binding domain of Pgp may play a role in catalytic transition and drug expulsion. The cytoplasmic recruitment theory was also tested, and the drugs were observed to interact with conserved loops of residues with a strong affinity. A free energy change of astronomical value is required to recruit the drug from the cytoplasm to the binding belt within the transmembrane domain of Pgp.
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| subjects | ABC transporters Binding sites Cancer therapies Cardiomyocytes cardiovascular drug binding Cytoplasm Drug resistance Energy Glycerol Glycoproteins Hypoxia Ligands mouse Pgp Original Pharmacology Proteins P‐glycoprotein Recruitment Scholarships & fellowships |
| title | Characterizing the binding interactions between P‐glycoprotein and eight known cardiovascular transport substrates |
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