Receptor Guided 3D-QSAR: A Useful Approach for Designing of IGF-1R Inhibitors

Abstract EN

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-α] 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) (q2=0.53, r2=0.95) and comparative molecular similarity indices analysis (CoMSIA) (q2=0.51, r2=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.