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Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2)
A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A(2) (hnps-PLA(2)) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA(2) complexed with a se...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
1995
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097651/ https://www.ncbi.nlm.nih.gov/pubmed/7664108 http://dx.doi.org/10.1038/nsb0695-458 |
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author | Schevitz, R.W. Bach, N.J. Carlson, D.G. Chirgadze, N.Y. Clawson, D.K. Dillard, R.D. Draheim, S.E. Hartley, L.W. Jones, N.D. Mihelich, E.D. Olkowski, J.L. Snyder, D.W. Sommers, C. Wery, J.-P. |
author_facet | Schevitz, R.W. Bach, N.J. Carlson, D.G. Chirgadze, N.Y. Clawson, D.K. Dillard, R.D. Draheim, S.E. Hartley, L.W. Jones, N.D. Mihelich, E.D. Olkowski, J.L. Snyder, D.W. Sommers, C. Wery, J.-P. |
author_sort | Schevitz, R.W. |
collection | PubMed |
description | A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A(2) (hnps-PLA(2)) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA(2) complexed with a series of increasingly potent indole inhibitors were determined and used as the structural basis for both understanding this binding and providing valuable insights for further development. The application of structure-based drug design has made possible improvements in the binding of this screening lead to the enzyme by nearly three orders of magnitude. Furthermore, the optimized structure (LY311727) displayed 1,500-fold selectivity when assayed against porcine pancreatic s-PLA(2). |
format | Online Article Text |
id | pubmed-7097651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1995 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-70976512020-03-26 Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2) Schevitz, R.W. Bach, N.J. Carlson, D.G. Chirgadze, N.Y. Clawson, D.K. Dillard, R.D. Draheim, S.E. Hartley, L.W. Jones, N.D. Mihelich, E.D. Olkowski, J.L. Snyder, D.W. Sommers, C. Wery, J.-P. Nat Struct Biol Article A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A(2) (hnps-PLA(2)) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA(2) complexed with a series of increasingly potent indole inhibitors were determined and used as the structural basis for both understanding this binding and providing valuable insights for further development. The application of structure-based drug design has made possible improvements in the binding of this screening lead to the enzyme by nearly three orders of magnitude. Furthermore, the optimized structure (LY311727) displayed 1,500-fold selectivity when assayed against porcine pancreatic s-PLA(2). Nature Publishing Group US 1995 /pmc/articles/PMC7097651/ /pubmed/7664108 http://dx.doi.org/10.1038/nsb0695-458 Text en © Nature Publishing Group 1995 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Article Schevitz, R.W. Bach, N.J. Carlson, D.G. Chirgadze, N.Y. Clawson, D.K. Dillard, R.D. Draheim, S.E. Hartley, L.W. Jones, N.D. Mihelich, E.D. Olkowski, J.L. Snyder, D.W. Sommers, C. Wery, J.-P. Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2) |
title | Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2) |
title_full | Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2) |
title_fullStr | Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2) |
title_full_unstemmed | Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2) |
title_short | Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A(2) |
title_sort | structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase a(2) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097651/ https://www.ncbi.nlm.nih.gov/pubmed/7664108 http://dx.doi.org/10.1038/nsb0695-458 |
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