title: Receptor guided 3D-QSAR: a useful approach for designing of IGF-1R inhibitors.
abstract: Research by other investigators has established that insulin-like growth factor-1 receptor (IGF-1R) is a key oncological target, and that derivatives of 1, 3-disubstituted-imidazo[1,5-alpha] pyrazine are potent IGF-1R inhibitors. In this paper, we report on our three-dimensional quantitative structure activity relationship (3D-QSAR) studies for this series of compounds. We validated the 3D-QSAR models by the comparison of two major alignment schemes, namely, ligand-based (LB) and receptor-guided (RG) alignment schemes. The latter scheme yielded better 3D-QSAR models for both comparative molecular field analysis (CoMFA) (q(2) = 0.35, r(2) = 0.95) and comparative molecular similarity indices analysis (CoMSIA) (q(2) = 0.51, r(2) = 0.86). We submit that this might arise from the more accurate inhibitor alignment that results from using the structural information of the active site. We conclude that the receptor-guided 3D-QSAR may be helpful to design more potent IGF-1R inhibitors, as well as to understand their binding affinity with the receptor.
authors.affiliation: Future Fusion Technology Division, Computational Science Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea.
authors.forename: M
authors.initials: M
authors.lastname: Muddassar
authors.forename: F A
authors.initials: FA
authors.lastname: Pasha
authors.forename: H W
authors.initials: HW
authors.lastname: Chung
authors.forename: K H
authors.initials: KH
authors.lastname: Yoo
authors.forename: C H
authors.initials: CH
authors.lastname: Oh
authors.forename: S J
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D017526:Receptor, IGF Type 1