title: CoMFA and docking studies on glycogen phosphorylase a inhibitors as antidiabetic agents.
abstract: Glycogen phosphorylase (GP(a)) is a specific target for the design of inhibitors and may prevent glycogenolysis under high glucose conditions in type II diabetes. The carboxamides first reported by Hoover D. J. et al. (J. Med. Chem. 1998, 41, 2934-2938) are one of the major classes of GP(a) inhibitors other than glucose derivatives. The recent, X-ray crystallographic analyses (Oikonomakos et al. Biochim. Biophys. Acta 2003, 1647, 325-332) have revealed a distinct mechanism of action for these inhibitors, which bind at a new allosteric site away from the inhibitory and catalytic sites. To elucidate the essential structural and physicochemical requirements responsible for binding to the GP(a) enzyme and to develop predictive models, CoMFA and docking studies have been carried out on a series of indole-2-carboxamide derivates. The CoMFA model developed using pharmacophoric alignments and hydrogen-bonding fields demonstrated high predictive ability against the training (r2 = 0.98, q2 = 0.68) and the test set (r2pred = 0.85). Further the superimposition of PLS coefficient contour maps from CoMFA with the GP(a) active site (PDB: 1lwo) has shown a high level of compatibility.
authors.affiliation: Medicinal Chemistry Division, Central Drug Research Institute, Chatter Manzil Palace, Lucknow-226 001, India.
authors.forename: Philip
authors.initials: P
authors.lastname: Prathipati
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Pandey
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D001665:Binding Sites; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010762:Phosphorylase a / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D007004:Hypoglycemic Agents; D010762:Phosphorylase a