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Binding Conformation of 2-Oxoamide Inhibitors to Group IVA Cytosolic Phospholipase A2 Determined by Molecular Docking Combined with Molecular Dynamics

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† Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
‡ Chemical Laboratories, Agricultural University of Athens, Athens, Greece
§ Department of Chemistry and Biochemistry and Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0601, United States
*Tel. (+30210) 7274462 (G.K.), (+30210) 7274475 (T.M.). E-mail: [email protected], [email protected]
Cite this: J. Chem. Inf. Model. 2012, 52, 1, 243–254
Publication Date (Web):December 24, 2011
https://doi.org/10.1021/ci2005093
Copyright © 2011 American Chemical Society
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    Abstract

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    The group IVA cytosolic phospholipase A2 (GIVA cPLA2) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA2 inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA2 active site through a combination of molecular docking calculations and molecular dynamics simulations. Recently, the location of the 2-oxoamide inhibitor AX007 within the active site of the GIVA cPLA2 was determined using a combination of deuterium exchange mass spectrometry followed by molecular dynamics simulations. After the optimization of the AX007-GIVA cPLA2 complex using the docking algorithm Surflex-Dock, a series of additional 2-oxoamide inhibitors have been docked in the enzyme active site. The calculated binding affinity presents a good statistical correlation with the experimental inhibitory activity (r2 = 0.76, N = 11). A molecular dynamics simulation of the docking complex of the most active compound has revealed persistent interactions of the inhibitor with the enzyme active site and proves the stability of the docking complex and the validity of the binding suggested by the docking calculations. The combination of molecular docking calculations and molecular dynamics simulations is useful in defining the binding of small-molecule inhibitors and provides a valuable tool for the design of new compounds with improved inhibitory activity against GIVA cPLA2.

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    Data and discussion for the interactions of 2-oxoamide inhibitors. This material is available free of charge via the Internet at http://pubs.acs.org.

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