title: Binding conformation of 2-oxoamide inhibitors to group IVA cytosolic phospholipase A2 determined by molecular docking combined with molecular dynamics.
abstract: 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).
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors.forename: Varnavas D
authors.initials: VD
authors.lastname: Mouchlis
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Michopoulou
authors.forename: Violetta
authors.initials: V
authors.lastname: Constantinou-Kokotou
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
mesh_terms: D000465:Algorithms; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; C034960:oxoamide; D054513:Group IV Phospholipases A2