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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
Author(s) -
Kantsadi Anastasia L.,
Hayes Joseph M.,
Manta Stella,
Skamnaki Vicky T.,
Kiritsis Christos,
Psarra AnnaMaria G.,
Koutsogiannis Zissis,
Dimopoulou Athina,
Theofanous Stavroula,
Nikoleousakos Nikolaos,
Zoumpoulakis Panagiotis,
Kontou Maria,
Papadopoulos George,
Zographos Spyros E.,
Komiotis Dimitris,
Leonidas Demetres D.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100533
Subject(s) - chemistry , halogen , stereochemistry , steric effects , glycogen phosphorylase , affinities , molecular mechanics , uracil , potency , computational chemistry , enzyme , alkyl , biochemistry , molecular dynamics , organic chemistry , in vitro , dna
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 μ M . 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 μ M ), 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.