Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2
- 1 June 1995
- journal article
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 2 (6), 458-465
- https://doi.org/10.1038/nsb0695-458
Abstract
A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A2 (hnps-PLA2) 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-PLA2 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-PLA2.Keywords
This publication has 29 references indexed in Scilit:
- Non-peptidic Inhibitors of Human Leukocyte Elastase. 1. The Design and Synthesis of Pyridone-Containing InhibitorsJournal of Medicinal Chemistry, 1994
- Groups I, II and III extracellular phospholipases A2: Selective inhibition of group II enzymes by indomethacin but not other NSAIDsInflammation Research, 1994
- Are Events After Endotoxemia Related to Circulating Phospholipase A2 ?Annals of Surgery, 1994
- Rational modification of human synovial fluid phospholipase A2 inhibitorsJournal of Medicinal Chemistry, 1994
- Rational Design of Potent, Bioavailable, Nonpeptide Cyclic Ureas as HIV Protease InhibitorsScience, 1994
- Rational design of potent sialidase-based inhibitors of influenza virus replicationNature, 1993
- Structure-Based Discovery of Inhibitors of Thymidylate SynthaseScience, 1993
- Fatty acid amides: scooting mode-based discovery of tight-binding competitive inhibitors of secreted phospholipases A2Journal of Medicinal Chemistry, 1992
- Structure of recombinant human rheumatoid arthritic synovial fluid phospholipase A2 at 2.2 Å resolutionNature, 1991
- Design, Activity, and 2.8 Å Crystal Structure of a C 2 Symmetric Inhibitor Complexed to HIV-1 ProteaseScience, 1990