Binding Conformation of 2-Oxoamide Inhibitors to Group IVA Cytosolic Phospholipase A2 Determined by Molecular Docking Combined with Molecular Dynamics
| Autor: | George Kokotos, Thomas Mavromoustakos, Varnavas D. Mouchlis, Vasiliki Michopoulou, Violetta Constantinou-Kokotou, Edward A. Dennis |
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| Rok vydání: | 2012 |
| Předmět: |
Pyridines
Stereochemistry Medicinal & Biomolecular Chemistry General Chemical Engineering Anti-Inflammatory Agents Molecular Conformation Molecular Dynamics Simulation Library and Information Sciences Article Substrate Specificity Medicinal and Biomolecular Chemistry Structure-Activity Relationship Molecular dynamics Phospholipase A2 Theoretical and Computational Chemistry In vivo Catalytic Domain Drug Discovery Humans Structure–activity relationship Enzyme Inhibitors biology Chemistry Drug discovery Group IV Phospholipases A2 Active site Computation Theory and Mathematics General Chemistry Computer Science Applications 5.1 Pharmaceuticals Docking (molecular) Drug Design biology.protein lipids (amino acids peptides and proteins) Hydrogen–deuterium exchange Hydrophobic and Hydrophilic Interactions Algorithms |
| Zdroj: | Journal of chemical information and modeling, vol 52, iss 1 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/ci2005093 |
| Popis: | The group IVA cytosolic phospholipase A(2) (GIVA cPLA(2)) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA(2) 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 cPLA(2) 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 cPLA(2) was determined using a combination of deuterium exchange mass spectrometry followed by molecular dynamics simulations. After the optimization of the AX007-GIVA cPLA(2) 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 (r(2) = 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 cPLA(2). |
| Databáze: | OpenAIRE |
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