Bioactive Conformation of Stromelysin Inhibitors Determined by Transferred Nuclear Overhauser Effects
The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1995-01, Vol.92 (2), p.462-466 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 92 |
| creator | Gonnella, Nina C. Bohacek, Regine Zhang, Xiaolu Kolossváry, István Paris, C. Gregory Melton, Richard Winter, Cindy Hu, Shou-Ih Ganu, Vishwas |
| description | The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design. |
| doi_str_mv | 10.1073/pnas.92.2.462 |
| format | Article |
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Gregory ; Melton, Richard ; Winter, Cindy ; Hu, Shou-Ih ; Ganu, Vishwas</creator><creatorcontrib>Gonnella, Nina C. ; Bohacek, Regine ; Zhang, Xiaolu ; Kolossváry, István ; Paris, C. Gregory ; Melton, Richard ; Winter, Cindy ; Hu, Shou-Ih ; Ganu, Vishwas</creatorcontrib><description>The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.92.2.462</identifier><identifier>PMID: 7831311</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Active sites ; Biology ; Computer Simulation ; Drug Design ; Enantiomers ; Enzymes ; Humans ; Hydroxamic Acids - chemistry ; Magnetic Resonance Spectroscopy - methods ; Matrix Metalloproteinase 3 ; Metalloendopeptidases - antagonists & inhibitors ; Metalloendopeptidases - chemistry ; Models, Molecular ; Molecular Conformation ; Molecules ; NMR ; Nuclear magnetic resonance ; Overhauser effect ; Phenyls ; Physics ; Protons ; Spectroscopy ; Stereoisomerism ; Structure-Activity Relationship ; Thermolysin - antagonists & inhibitors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1995-01, Vol.92 (2), p.462-466</ispartof><rights>Copyright 1995 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jan 17, 1995</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-315a47c80912d438954eadac2aa1a983ffe9aa693c4616e25c195ee005a6b4833</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/92/2.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2366644$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2366644$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7831311$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gonnella, Nina C.</creatorcontrib><creatorcontrib>Bohacek, Regine</creatorcontrib><creatorcontrib>Zhang, Xiaolu</creatorcontrib><creatorcontrib>Kolossváry, István</creatorcontrib><creatorcontrib>Paris, C. Gregory</creatorcontrib><creatorcontrib>Melton, Richard</creatorcontrib><creatorcontrib>Winter, Cindy</creatorcontrib><creatorcontrib>Hu, Shou-Ih</creatorcontrib><creatorcontrib>Ganu, Vishwas</creatorcontrib><title>Bioactive Conformation of Stromelysin Inhibitors Determined by Transferred Nuclear Overhauser Effects</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design.</description><subject>Active sites</subject><subject>Biology</subject><subject>Computer Simulation</subject><subject>Drug Design</subject><subject>Enantiomers</subject><subject>Enzymes</subject><subject>Humans</subject><subject>Hydroxamic Acids - chemistry</subject><subject>Magnetic Resonance Spectroscopy - methods</subject><subject>Matrix Metalloproteinase 3</subject><subject>Metalloendopeptidases - antagonists & inhibitors</subject><subject>Metalloendopeptidases - chemistry</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecules</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Overhauser effect</subject><subject>Phenyls</subject><subject>Physics</subject><subject>Protons</subject><subject>Spectroscopy</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Thermolysin - antagonists & inhibitors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1vEzEQhi0EKiFw5AbSCgluG_y13rXEBUKBShU9UM7WxJkljnbt1vZG5N_jqGn4OHCyrOd5RzN6CXnO6ILRVry98ZAWmi_4Qir-gMwY1axWUtOHZEYpb-tOcvmYPElpSynVTUfPyFnbCSYYmxH84ALY7HZYLYPvQxwhu-Cr0FffcgwjDvvkfHXhN27lcoip-ogZ4-g8rqvVvrqO4FOPMZbv18kOCLG62mHcwJQwVud9jzanp-RRD0PCZ8d3Tr5_Or9efqkvrz5fLN9f1la2OteCNSBb25UL-FqKTjcSYQ2WAzDQnSjDNIDSwkrFFPLGMt0gUtqAWslOiDl5dzf3ZlqNuLboc4TB3EQ3QtybAM78TbzbmB9hZyRvFS3xN8d4DLcTpmxGlywOA3gMUzJty1gnyiJz8uofcRum6MtphlMmqO5aXaT6TrIxpBSxP-3BqDlUZw7VGc0NN6W64r_8c_mTfeyq8NdHfojd0_u46adhyPgzF-_Ff7zfeJtKnyfOhVJKSvELhne3sw</recordid><startdate>19950117</startdate><enddate>19950117</enddate><creator>Gonnella, Nina C.</creator><creator>Bohacek, Regine</creator><creator>Zhang, Xiaolu</creator><creator>Kolossváry, István</creator><creator>Paris, C. 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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1995-01, Vol.92 (2), p.462-466 |
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| source | MEDLINE; Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Active sites Biology Computer Simulation Drug Design Enantiomers Enzymes Humans Hydroxamic Acids - chemistry Magnetic Resonance Spectroscopy - methods Matrix Metalloproteinase 3 Metalloendopeptidases - antagonists & inhibitors Metalloendopeptidases - chemistry Models, Molecular Molecular Conformation Molecules NMR Nuclear magnetic resonance Overhauser effect Phenyls Physics Protons Spectroscopy Stereoisomerism Structure-Activity Relationship Thermolysin - antagonists & inhibitors |
| title | Bioactive Conformation of Stromelysin Inhibitors Determined by Transferred Nuclear Overhauser Effects |
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