Design, Synthesis, and Conformational Analysis of a Novel Macrocyclic HIV-Protease Inhibitor
Design modifications to the lead HIV-PR inhibitor 1 (MDL 73,669, Ki = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P1 and P3 side chains of the original acyclic inhibitor have been joined retains good bio...
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| Veröffentlicht in: | Journal of medicinal chemistry 1994-10, Vol.37 (22), p.3684-3692 |
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| container_end_page | 3692 |
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| container_issue | 22 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Podlogar, Brent L Farr, Robert A Friedrich, Dirk Tarnus, Celine Huber, Edward W Cregge, Robert J Schirlin, Daniel |
| description | Design modifications to the lead HIV-PR inhibitor 1 (MDL 73,669, Ki = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P1 and P3 side chains of the original acyclic inhibitor have been joined retains good biological activity (Ki = 20 nM). NMR analysis of the precursor alcohol (S)-7 shows the conformation of the cyclic region to be very similar to that observed in the enzyme-bound 8 as determined by the computational model. Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR. |
| doi_str_mv | 10.1021/jm00048a004 |
| format | Article |
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Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR.</description><subject>AIDS/HIV</subject><subject>Amino Acid Sequence</subject><subject>Dipeptides - chemistry</subject><subject>Dipeptides - pharmacology</subject><subject>Drug Design</subject><subject>HIV Protease Inhibitors - chemistry</subject><subject>HIV Protease Inhibitors - pharmacology</subject><subject>human immunodeficiency virus</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEFPGzEQRi3UCgLlxLmST-UAS8feXdsco0CbSCEFEuBSyfI6s2XD7jrYm6r593WUCHGo1MvMSN_TjOYRcsLgggFnXxcNAGTKxLJHeiznkGQKsg-kB8B5wgVPD8hhCIuIpYyn-2RfXgrBuOqRn1cYql_tOZ2u2-45zuGcmnZOB64tnW9MV7nW1LQfyzqG1JXU0In7jTW9MdY7u7Z1Zelw9JjcetehCUhH7XNVVJ3zn8jH0tQBj3f9iDx8u54Nhsn4x_fRoD9OTKryLuGYosoRABnjl5jNRV7mUqSKIRYlV2DzAucCFDClsrJgUnGLVhQZl1bYLD0iX7Z7l969rjB0uqmCxbo2LbpV0FKojQT4L8iEBAlKRvBsC8YXQ_BY6qWvGuPXmoHeSNfvpEf6827tqmhw_sbuLMc82eZV6PDPW2z8ixYylbme3U71dDB5msi7qb6P_OmWNzbohVv5aD_88_JfawCXRw</recordid><startdate>19941001</startdate><enddate>19941001</enddate><creator>Podlogar, Brent L</creator><creator>Farr, Robert A</creator><creator>Friedrich, Dirk</creator><creator>Tarnus, Celine</creator><creator>Huber, Edward W</creator><creator>Cregge, Robert J</creator><creator>Schirlin, Daniel</creator><general>American Chemical Society</general><scope>BSCLL</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>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>19941001</creationdate><title>Design, Synthesis, and Conformational Analysis of a Novel Macrocyclic HIV-Protease Inhibitor</title><author>Podlogar, Brent L ; Farr, Robert A ; Friedrich, Dirk ; Tarnus, Celine ; Huber, Edward W ; Cregge, Robert J ; Schirlin, Daniel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a385t-2e3e85e00e1129e4d65f576381eebf280c5bed60801884fb1782cec6b427c6c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>AIDS/HIV</topic><topic>Amino Acid Sequence</topic><topic>Dipeptides - chemistry</topic><topic>Dipeptides - pharmacology</topic><topic>Drug Design</topic><topic>HIV Protease Inhibitors - chemistry</topic><topic>HIV Protease Inhibitors - pharmacology</topic><topic>human immunodeficiency virus</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Podlogar, Brent L</creatorcontrib><creatorcontrib>Farr, Robert A</creatorcontrib><creatorcontrib>Friedrich, Dirk</creatorcontrib><creatorcontrib>Tarnus, Celine</creatorcontrib><creatorcontrib>Huber, Edward W</creatorcontrib><creatorcontrib>Cregge, Robert J</creatorcontrib><creatorcontrib>Schirlin, Daniel</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Podlogar, Brent L</au><au>Farr, Robert A</au><au>Friedrich, Dirk</au><au>Tarnus, Celine</au><au>Huber, Edward W</au><au>Cregge, Robert J</au><au>Schirlin, Daniel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Conformational Analysis of a Novel Macrocyclic HIV-Protease Inhibitor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-10-01</date><risdate>1994</risdate><volume>37</volume><issue>22</issue><spage>3684</spage><epage>3692</epage><pages>3684-3692</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Design modifications to the lead HIV-PR inhibitor 1 (MDL 73,669, Ki = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P1 and P3 side chains of the original acyclic inhibitor have been joined retains good biological activity (Ki = 20 nM). NMR analysis of the precursor alcohol (S)-7 shows the conformation of the cyclic region to be very similar to that observed in the enzyme-bound 8 as determined by the computational model. Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>7966128</pmid><doi>10.1021/jm00048a004</doi><tpages>9</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1994-10, Vol.37 (22), p.3684-3692 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | AIDS/HIV Amino Acid Sequence Dipeptides - chemistry Dipeptides - pharmacology Drug Design HIV Protease Inhibitors - chemistry HIV Protease Inhibitors - pharmacology human immunodeficiency virus Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology |
| title | Design, Synthesis, and Conformational Analysis of a Novel Macrocyclic HIV-Protease Inhibitor |
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