title: The σ-hole phenomenon of halogen atoms forms the structural basis of the strong inhibitory potency of C5 halogen substituted glucopyranosyl nucleosides towards glycogen phosphorylase b.
abstract: C5 halogen substituted glucopyranosyl nucleosides (1-(β-D-glucopyranosyl)-5-X-uracil; X=Cl, Br, I) have been discovered as some of the most potent active site inhibitors of glycogen phosphorylase (GP), with respective K(i) values of 1.02, 3.27, and 1.94 μM. The ability of the halogen atom to form intermolecular electrostatic interactions through the σ-hole phenomenon rather than through steric effects alone forms the structural basis of their improved inhibitory potential relative to the unsubstituted 1-(β-D-glucopyranosyl)uracil (K(i) =12.39 μM), as revealed by X-ray crystallography and modeling calculations exploiting quantum mechanics methods. Good agreement was obtained between kinetics results and relative binding affinities calculated by QM/MM-PBSA methodology for various substitutions at C5. Ex vivo experiments demonstrated that the most potent derivative (X=Cl) toward purified GP has no cytotoxicity and moderate inhibitory potency at the cellular level. In accordance, ADMET property predictions were performed, and suggest decreased polar surface areas as a potential means of improving activity in the cell.
authors.affiliation: Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Anastasia L
authors.initials: AL
authors.lastname: Kantsadi
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Hayes
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
authors.forename: Vicky T
authors.initials: VT
authors.lastname: Skamnaki
authors.forename: Christos
authors.initials: C
authors.lastname: Kiritsis
authors.forename: Anna-Maria G
authors.initials: AM
authors.lastname: Psarra
authors.forename: Zissis
authors.initials: Z
authors.lastname: Koutsogiannis
authors.forename: Athina
authors.initials: A
authors.lastname: Dimopoulou
authors.forename: Stavroula
authors.initials: S
authors.lastname: Theofanous
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Nikoleousakos
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Zoumpoulakis
authors.forename: Maria
authors.initials: M
authors.lastname: Kontou
authors.forename: George
authors.initials: G
authors.lastname: Papadopoulos
authors.forename: Spyros E
authors.initials: SE
authors.lastname: Zographos
authors.forename: Dimitris
authors.initials: D
authors.lastname: Komiotis
authors.forename: Demetres D
authors.initials: DD
authors.lastname: Leonidas
mesh_terms: D020134:Catalytic Domain; D002460:Cell Line; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D006219:Halogens / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D010763:Phosphorylase b / Q000037:antagonists & inhibitors; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006219:Halogens; D008024:Ligands; D009705:Nucleosides; D024981:Glycogen Phosphorylase; D010763:Phosphorylase b