title: Influenza neuraminidase inhibitors: structure-based design of a novel inhibitor series.
abstract: Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.
authors.affiliation: Department of Advanced Technology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Stoll
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Maring
authors.forename: Steven
authors.initials: S
authors.lastname: Muchmore
authors.forename: Vincent
authors.initials: V
authors.lastname: Giranda
authors.forename: Yu-gui Y
authors.initials: YG
authors.lastname: Gu
authors.forename: Gary
authors.initials: G
authors.lastname: Wang
authors.forename: Yuanwei
authors.initials: Y
authors.lastname: Chen
authors.forename: Minghua
authors.initials: M
authors.lastname: Sun
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: April L
authors.initials: AL
authors.lastname: Kennedy
authors.forename: Darold L
authors.initials: DL
authors.lastname: Madigan
authors.forename: Yibo
authors.initials: Y
authors.lastname: Xu
authors.forename: Ayda
authors.initials: A
authors.lastname: Saldivar
authors.forename: Warren
authors.initials: W
authors.lastname: Kati
authors.forename: Graeme
authors.initials: G
authors.lastname: Laver
authors.forename: Thomas
authors.initials: T
authors.lastname: Sowin
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Jonathan
authors.initials: J
authors.lastname: Greer
authors.forename: Dale
authors.initials: D
authors.lastname: Kempf
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D001717:Birds; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003460:Crystallization; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004952:Esters; D009980:Influenza A virus / Q000201:enzymology*; D008958:Models, Molecular; D036103:Nanotechnology / Q000379:methods; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000302:isolation & purification; D011759:Pyrrolidines / Q000138:chemical synthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D004952:Esters; D011759:Pyrrolidines; D009439:Neuraminidase