title: Guanidinobenzoic acid inhibitors of influenza virus neuraminidase.
abstract: The active site of influenza virus neuraminidase (NA) is formed by 11 universally conserved residues. A guanidino group incorporated into two unrelated NA inhibitors was previously reported to occupy different negatively charged sites in the NA active site, A new inhibitor containing two guanidino groups was synthesized in order to utilize both sites in an attempt to acquire a combined increase in affinity. The X-ray crystal structures of the complexes show that the expected increase in affinity could not be achieved even though the added guanidino group binds to the negatively charged site as designed. This suggests that the ligand affinity to the target protein is contributed both from ligand-protein interactions and solvation/conformation energy of the ligand.
authors.affiliation: Center for Macromolecular Crystallography, University of Alabama at Birmingham, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Sudbeck
authors.forename: M J
authors.initials: MJ
authors.lastname: Jedrzejas
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: W J
authors.initials: WJ
authors.lastname: Brouillette
authors.forename: G M
authors.initials: GM
authors.lastname: Air
authors.forename: W G
authors.initials: WG
authors.lastname: Laver
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
authors.forename: S
authors.initials: S
authors.lastname: Bantia
authors.forename: P
authors.initials: P
authors.lastname: Chand
authors.forename: N
authors.initials: N
authors.lastname: Chu
authors.forename: J A
authors.initials: JA
authors.lastname: Montgomery
authors.forename: D A
authors.initials: DA
authors.lastname: Walsh
authors.forename: M
authors.initials: M
authors.lastname: Luo
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062385:Hydroxybenzoates / Q000737:chemistry / Q000494:pharmacology*; D009981:Influenza B virus / Q000201:enzymology*; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: C105580:3,5-diguanidino-4-(N-acetylamino)benzoic acid; C098391:4-(acetylamino)-5-guanidino-3-hydroxybenzoic acid; D004791:Enzyme Inhibitors; D006146:Guanidines; D062385:Hydroxybenzoates; D014867:Water; D009439:Neuraminidase