Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment
Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist...
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| Veröffentlicht in: | European journal of medicinal chemistry 2006, Vol.41 (1), p.16-26 |
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| container_title | European journal of medicinal chemistry |
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| creator | ISKANDER, Magdy N LEUNG, Lok M BULEY, Trevor AYAD, Fadi DI IULIO, Juliana TAN, Yean Y COUPAR, Ian M |
| description | Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT4 receptor (model B). Comparison of the two models showed that the q2 value for model A was 0.564 vs. 0.582 for model B. Model B indicated that the predictive power model stems from far lower steric contributions, 0.270 compared to model A's 0.502. The dominant defining features were the electrostatic contributions for model B, 0.664 up from 0.477 in model A. The contributions from the LogP factor were minimal, 0.085 in both models. The synthesized compounds showed agonist activity at mumol level. |
| doi_str_mv | 10.1016/j.ejmech.2005.07.017 |
| format | Article |
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Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT4 receptor (model B). Comparison of the two models showed that the q2 value for model A was 0.564 vs. 0.582 for model B. Model B indicated that the predictive power model stems from far lower steric contributions, 0.270 compared to model A's 0.502. The dominant defining features were the electrostatic contributions for model B, 0.664 up from 0.477 in model A. The contributions from the LogP factor were minimal, 0.085 in both models. The synthesized compounds showed agonist activity at mumol level.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2005.07.017</identifier><identifier>PMID: 16293350</identifier><identifier>CODEN: EJMCA5</identifier><language>eng</language><publisher>Oxford: Elsevier</publisher><subject>Binding Sites ; Biological and medical sciences ; Dopamine Plasma Membrane Transport Proteins ; Drug Design ; Ligands ; Medical sciences ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Quantitative Structure-Activity Relationship ; Receptors, Serotonin, 5-HT4 - chemistry ; Receptors, Serotonin, 5-HT4 - metabolism ; Serotonin 5-HT4 Receptor Agonists ; Serotonin Receptor Agonists - chemical synthesis ; Serotonin Receptor Agonists - chemistry ; Serotonin Receptor Agonists - pharmacology ; Serotoninergic system</subject><ispartof>European journal of medicinal chemistry, 2006, Vol.41 (1), p.16-26</ispartof><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c335t-bbbb5fc5b29e287c2587742d9813eeb6c6852aae075bdf1a8f488c75ffff079c3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17548434$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16293350$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ISKANDER, Magdy N</creatorcontrib><creatorcontrib>LEUNG, Lok M</creatorcontrib><creatorcontrib>BULEY, Trevor</creatorcontrib><creatorcontrib>AYAD, Fadi</creatorcontrib><creatorcontrib>DI IULIO, Juliana</creatorcontrib><creatorcontrib>TAN, Yean Y</creatorcontrib><creatorcontrib>COUPAR, Ian M</creatorcontrib><title>Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT4 receptor (model B). Comparison of the two models showed that the q2 value for model A was 0.564 vs. 0.582 for model B. Model B indicated that the predictive power model stems from far lower steric contributions, 0.270 compared to model A's 0.502. The dominant defining features were the electrostatic contributions for model B, 0.664 up from 0.477 in model A. The contributions from the LogP factor were minimal, 0.085 in both models. The synthesized compounds showed agonist activity at mumol level.</description><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Dopamine Plasma Membrane Transport Proteins</subject><subject>Drug Design</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Receptors, Serotonin, 5-HT4 - chemistry</subject><subject>Receptors, Serotonin, 5-HT4 - metabolism</subject><subject>Serotonin 5-HT4 Receptor Agonists</subject><subject>Serotonin Receptor Agonists - chemical synthesis</subject><subject>Serotonin Receptor Agonists - chemistry</subject><subject>Serotonin Receptor Agonists - pharmacology</subject><subject>Serotoninergic system</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1P3DAURa2qVRlo_0FVedPuEvwZO0s0goIEYgNr68V5nvEoiVM7s2h_PUEzEnfzNudePR1CfnBWc8ab60ONhxH9vhaM6ZqZmnHziWy4aWwlhVafyYYJISstpLogl6Uc2Ao2jH0lF7wRrZSabQg8z0sc439YYppoChTovIc8gk_zPmWkY-pxoCFlqqv7F0Vhl6ZYlkKPJU47uk1PdzcUpp5m9DgvK9dBwZ7CEHfTiNPyjXwJMBT8fr5X5PXu9mV7Xz0-_3nY3jxWfv1kqbo1OnjdiRaFNV5oa4wSfWu5ROwa31gtAJAZ3fWBgw3KWm90WMNM6-UV-X3anXP6e8SyuDEWj8MAE6ZjcY1pWiZasYLqBPqcSskY3JzjCPmf48y9q3UHd1Lr3tU6Ztyqdq39PO8fuxH7j9LZ5Qr8OgNQPAwhw-Rj-eCMVlZJJd8Am7aETw</recordid><startdate>2006</startdate><enddate>2006</enddate><creator>ISKANDER, Magdy N</creator><creator>LEUNG, Lok M</creator><creator>BULEY, Trevor</creator><creator>AYAD, Fadi</creator><creator>DI IULIO, Juliana</creator><creator>TAN, Yean Y</creator><creator>COUPAR, Ian M</creator><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>2006</creationdate><title>Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment</title><author>ISKANDER, Magdy N ; LEUNG, Lok M ; BULEY, Trevor ; AYAD, Fadi ; DI IULIO, Juliana ; TAN, Yean Y ; COUPAR, Ian M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c335t-bbbb5fc5b29e287c2587742d9813eeb6c6852aae075bdf1a8f488c75ffff079c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Dopamine Plasma Membrane Transport Proteins</topic><topic>Drug Design</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Structure</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Quantitative Structure-Activity Relationship</topic><topic>Receptors, Serotonin, 5-HT4 - chemistry</topic><topic>Receptors, Serotonin, 5-HT4 - metabolism</topic><topic>Serotonin 5-HT4 Receptor Agonists</topic><topic>Serotonin Receptor Agonists - chemical synthesis</topic><topic>Serotonin Receptor Agonists - chemistry</topic><topic>Serotonin Receptor Agonists - pharmacology</topic><topic>Serotoninergic system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ISKANDER, Magdy N</creatorcontrib><creatorcontrib>LEUNG, Lok M</creatorcontrib><creatorcontrib>BULEY, Trevor</creatorcontrib><creatorcontrib>AYAD, Fadi</creatorcontrib><creatorcontrib>DI IULIO, Juliana</creatorcontrib><creatorcontrib>TAN, Yean Y</creatorcontrib><creatorcontrib>COUPAR, Ian M</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ISKANDER, Magdy N</au><au>LEUNG, Lok M</au><au>BULEY, Trevor</au><au>AYAD, Fadi</au><au>DI IULIO, Juliana</au><au>TAN, Yean Y</au><au>COUPAR, Ian M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2006</date><risdate>2006</risdate><volume>41</volume><issue>1</issue><spage>16</spage><epage>26</epage><pages>16-26</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><coden>EJMCA5</coden><abstract>Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT4 receptor (model B). Comparison of the two models showed that the q2 value for model A was 0.564 vs. 0.582 for model B. Model B indicated that the predictive power model stems from far lower steric contributions, 0.270 compared to model A's 0.502. The dominant defining features were the electrostatic contributions for model B, 0.664 up from 0.477 in model A. The contributions from the LogP factor were minimal, 0.085 in both models. The synthesized compounds showed agonist activity at mumol level.</abstract><cop>Oxford</cop><pub>Elsevier</pub><pmid>16293350</pmid><doi>10.1016/j.ejmech.2005.07.017</doi><tpages>11</tpages></addata></record> |
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| subjects | Binding Sites Biological and medical sciences Dopamine Plasma Membrane Transport Proteins Drug Design Ligands Medical sciences Models, Molecular Molecular Conformation Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Quantitative Structure-Activity Relationship Receptors, Serotonin, 5-HT4 - chemistry Receptors, Serotonin, 5-HT4 - metabolism Serotonin 5-HT4 Receptor Agonists Serotonin Receptor Agonists - chemical synthesis Serotonin Receptor Agonists - chemistry Serotonin Receptor Agonists - pharmacology Serotoninergic system |
| title | Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment |
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