title: Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.
abstract: Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Alison J-A
authors.initials: AJ
authors.lastname: Woolford
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Pero
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Aravapalli
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Valerio
authors.initials: V
authors.lastname: Berdini
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Coyle
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Dodson
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Grondin
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Finn P
authors.initials: FP
authors.lastname: Holding
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Lydia Y W
authors.initials: LY
authors.lastname: Lee
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.affiliation: GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Marino
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Agnes C L
authors.initials: AC
authors.lastname: Martin
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Brent W
authors.initials: BW
authors.lastname: McCleland
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: McMenamin
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Neipp
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Lee W
authors.initials: LW
authors.lastname: Page
authors.affiliation: GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
authors.forename: Vipulkumar K
authors.initials: VK
authors.lastname: Patel
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Potvain
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Sharna
authors.initials: S
authors.lastname: Rich
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Smith
authors.affiliation: GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
authors.forename: Donald O
authors.initials: DO
authors.lastname: Somers
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Trottet
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Ranganadh
authors.initials: R
authors.lastname: Velagaleti
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Glyn
authors.initials: G
authors.lastname: Williams
authors.affiliation: GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human