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Modeling of substrate and inhibitor binding to phospholipase A 2
Author(s) -
Sessions Richard B.,
DauberOsguuthorpe Pnina,
Campbell Malcolm M.,
Osguthorpe David J.
Publication year - 1992
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.340140107
Subject(s) - chemistry , enzyme , stereochemistry , molecular model , substrate (aquarium) , mechanism of action , docking (animal) , rational design , phospholipase , binding site , phospholipase a , phospholipase a2 , combinatorial chemistry , biochemistry , materials science , nanotechnology , biology , medicine , in vitro , ecology , nursing
Molecular graphics and molecular mechanics techniques have been used to study the mode of ligand binding and mechanism of action of the enzyme phospholipase A 2 . A substrate–enzyme complex was constructed based on the crystal structure of the apoenzyme. The complex was minimized to relieve initial strain, and the structural and energetic features of the resultant complex analyzed in detail, at the molecular and residue level. The minimized complex was then used as a basis for examining the action of the enzyme on modified substrates, binding of inhibitors to the enzyme, and possible reaction intermedite complexes. The model is compatible with the suggested mechanism of hydrolysis and with experimental data about stereoselectivity, efficiency of hydrolysis of modified substrates, and inhibitor potency. In conclusion, the model can be used as a tool in evaluating new ligands as possible substrates and in the rational design of inhibitors, for the therapeutic treatment of diseases such as rheumatoid arthritis, atherosclerosis, and asthma. © 1992 Wiley‐Liss, Inc.