Receptor guided 3D-QSAR: a useful approach for designing of IGF-1R inhibitors.
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.
Muddassar
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Future Fusion Technology Division, Computational Science Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea.
Pasha
F A
FA
Chung
H W
HW
Yoo
K H
KH
Oh
C H
CH
Cho
S J
SJ
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*
D047428:Protein Kinase Inhibitors; D017526:Receptor, IGF Type 1