A Ligand-Based Approach To Identify Quantitative Structure−Activity Relationships for the Androgen Receptor
We examined the three-dimensional quantitative structure−activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high b...
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| Veröffentlicht in: | Journal of medicinal chemistry 2004-07, Vol.47 (15), p.3765-3776 |
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| container_issue | 15 |
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| container_title | Journal of medicinal chemistry |
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| creator | Bohl, Casey E. Chang, Cheng Mohler, Michael L. Chen, Jiyun Miller, Duane D. Swaan, Peter W. Dalton, James T. |
| description | We examined the three-dimensional quantitative structure−activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r 2 and cross-validated q 2 relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r 2 of 0.954, demonstrating the excellent predictive ability of the model. These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs. |
| doi_str_mv | 10.1021/jm0499007 |
| format | Article |
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The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r 2 and cross-validated q 2 relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r 2 of 0.954, demonstrating the excellent predictive ability of the model. 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Med. Chem</addtitle><description>We examined the three-dimensional quantitative structure−activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r 2 and cross-validated q 2 relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r 2 of 0.954, demonstrating the excellent predictive ability of the model. These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs.</description><subject>Anilides - chemistry</subject><subject>Biological and medical sciences</subject><subject>Heterocyclic Compounds, 3-Ring - chemistry</subject><subject>Hormones. Endocrine system</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Nitriles</subject><subject>Pharmacology. Drug treatments</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Quinolines - chemistry</subject><subject>Receptors, Androgen - chemistry</subject><subject>Static Electricity</subject><subject>Steroids - chemistry</subject><subject>Tosyl Compounds</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc2O0zAUhSMEYjoDC14AZQMSi8C1HbvJBikzYmBE-W2R2Fk3jtO6JHGwnRF9A9Y8Ik-CUavOILG61j2fjo99kuQRgecEKHmx7SEvS4D5nWRGOIUsLyC_m8wAKM2ooOwkOfV-CwCMUHY_OYkQKwXns6Sv0oVZ49Bk5-h1k1bj6CyqTbqy6VWjh2DaXfppwngIGMy1TpfBTSpMTv_--atScWXCLv2su6jawW_M6NPWujRsdFoNjbNrPURZ6TFY9yC512Ln9cPDPEu-XL5aXbzJFh9eX11Uiww54yHDRte6bBtogKEqc60VtkiVagUhPFdtXigOtdDAEVXNiJgLjoJCTeqCkJadJS_3vuNU97pR8R0OOzk606PbSYtG_qsMZiPX9lpSKGBeQDR4ejBw9vukfZC98Up3HQ7aTl4KIQqe5ySCz_agctZ7p9vjJQTk33LksZzIPr6d6oY8tBGBJwcAvcKudTgo429xZQ5QiMhle874oH8cdXTfpJizOZerj0v5tmDk_dd3hVze-KLycmsnN8TP_0_AP8hPthY</recordid><startdate>20040715</startdate><enddate>20040715</enddate><creator>Bohl, Casey E.</creator><creator>Chang, Cheng</creator><creator>Mohler, Michael L.</creator><creator>Chen, Jiyun</creator><creator>Miller, Duane D.</creator><creator>Swaan, Peter W.</creator><creator>Dalton, James T.</creator><general>American Chemical Society</general><scope>BSCLL</scope><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><scope>5PM</scope></search><sort><creationdate>20040715</creationdate><title>A Ligand-Based Approach To Identify Quantitative Structure−Activity Relationships for the Androgen Receptor</title><author>Bohl, Casey E. ; Chang, Cheng ; Mohler, Michael L. ; Chen, Jiyun ; Miller, Duane D. ; Swaan, Peter W. ; Dalton, James T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a535t-adebe9fd0d03ac94eecafa2ccf61154cf48c50b6e05aacb316765a620b1b811f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Anilides - chemistry</topic><topic>Biological and medical sciences</topic><topic>Heterocyclic Compounds, 3-Ring - chemistry</topic><topic>Hormones. Endocrine system</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Structure</topic><topic>Nitriles</topic><topic>Pharmacology. Drug treatments</topic><topic>Quantitative Structure-Activity Relationship</topic><topic>Quinolines - chemistry</topic><topic>Receptors, Androgen - chemistry</topic><topic>Static Electricity</topic><topic>Steroids - chemistry</topic><topic>Tosyl Compounds</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bohl, Casey E.</creatorcontrib><creatorcontrib>Chang, Cheng</creatorcontrib><creatorcontrib>Mohler, Michael L.</creatorcontrib><creatorcontrib>Chen, Jiyun</creatorcontrib><creatorcontrib>Miller, Duane D.</creatorcontrib><creatorcontrib>Swaan, Peter W.</creatorcontrib><creatorcontrib>Dalton, James T.</creatorcontrib><collection>Istex</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bohl, Casey E.</au><au>Chang, Cheng</au><au>Mohler, Michael L.</au><au>Chen, Jiyun</au><au>Miller, Duane D.</au><au>Swaan, Peter W.</au><au>Dalton, James T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Ligand-Based Approach To Identify Quantitative Structure−Activity Relationships for the Androgen Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2004-07-15</date><risdate>2004</risdate><volume>47</volume><issue>15</issue><spage>3765</spage><epage>3776</epage><pages>3765-3776</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>We examined the three-dimensional quantitative structure−activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r 2 and cross-validated q 2 relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r 2 of 0.954, demonstrating the excellent predictive ability of the model. These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>15239655</pmid><doi>10.1021/jm0499007</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anilides - chemistry Biological and medical sciences Heterocyclic Compounds, 3-Ring - chemistry Hormones. Endocrine system Ligands Medical sciences Models, Molecular Molecular Conformation Molecular Structure Nitriles Pharmacology. Drug treatments Quantitative Structure-Activity Relationship Quinolines - chemistry Receptors, Androgen - chemistry Static Electricity Steroids - chemistry Tosyl Compounds |
| title | A Ligand-Based Approach To Identify Quantitative Structure−Activity Relationships for the Androgen Receptor |
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