title: Location of inhibitors bound to group IVA phospholipase A2 determined by molecular dynamics and deuterium exchange mass spectrometry.
abstract: An analysis of group IVA (GIVA) phospholipase A(2) (PLA(2)) inhibitor binding was conducted using a combination of deuterium exchange mass spectrometry (DXMS) and molecular dynamics (MD). Models of the GIVA PLA(2) inhibitors pyrrophenone and the 2-oxoamide AX007 docked into the protein were designed on the basis of deuterium exchange results, and extensive molecular dynamics simulations were run to determine protein-inhibitor contacts. The models show that both inhibitors interact with key residues that also exhibit changes in deuterium exchange upon inhibitor binding. Pyrrophenone is bound to the protein through numerous hydrophobic residues located distal from the active site, while the oxoamide is bound mainly through contacts near the active site. We also show differences in protein dynamics around the active site between the two inhibitor-bound complexes. This combination of computational and experimental methods is useful in defining more accurate inhibitor binding sites and can be used in the generation of better inhibitors against GIVA PLA(2).
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive MC 0601, La Jolla, California 92093-0601, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Burke
authors.forename: Arneh
authors.initials: A
authors.lastname: Babakhani
authors.forename: Alemayehu A
authors.initials: AA
authors.lastname: Gorfe
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Woods
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002210:Caprylates / Q000737:chemistry / Q000494:pharmacology; D003903:Deuterium / Q000737:chemistry; D041961:Deuterium Exchange Measurement; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: C488114:4-((2-oxododecanoyl)amino)octanoic acid; D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D002210:Caprylates; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; C455981:pyrrophenone; D003903:Deuterium; D054513:Group IV Phospholipases A2; C531068:efipladib