The Receptor Guided 3D-QSAR Method is a Powerful Tool to Design More Potent IGF-1R Inhibitors

• Main Authors: Muddassar, M., Pasha, F.A., Hwan Won Chung, Kyung Ho Yoo, Chang Hyun Oh, Seung Joo Cho
• Format: Conference Proceeding
• Language: English
• Subjects: Amino acids; Biomembranes; Cancer; Fasteners; Humans; Hydrogen; Information technology; Inhibitors; Oncology; Proteins
• DOI: 10.1109/FBIT.2007.138

Insulin-like growth factor-1 receptor (IGF-1R) has proven as a key oncology target. Recently derivatives of 1,3-disubstituted-imidazo[1,5-alpha] pyrazine have been found as potent IGF-IR inhibitors. Three dimensional quantitative structure activity relationship (3D-QSAR) studies have been performed for this series of compounds and validity of 3D-QSAR models compared for two major alignment schemes, namely ligand-based and receptor-guided alignment schemes. As a result, receptor guided alignment schemes yielded better 3D-QSAR models for both comparative molecular field analysis (CoMFA) (q 2 =0.53, r 2 =0.95) and comparative molecular similarity indices analysis (CoMSIA) (q 2 =0.51, r 2 =0.86). This might arise from the more accurate inhibitor alignment using structural information of the active site. Therefore the receptor-guided 3D- QSAR may be helpful to design more potent IGF-IR inhibitors as well as to understand the inhibitor binding.