Case Study: Extraction of IGFR inhibitors from a database

The Insulin-like Growth Factor 1 receptor (IGF-1) is a transmembrane receptor that is activated by IGF-1 and by the related growth factor IGF-II. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is structurally related to insulin. IGF-1R plays crucial roles in embryonic development, differentiation, postnatal growth as well as aging and transformation and growth of malignant cells. IGF-1R is considered to be a promising target for anticancer treatment.

An inhibitors identification of Insulin-like Growth Factor Receptors (IGFR) from a database containing 800.000 compounds.

The scheme below illustrates the procedure used. In a first step the database was divided into clusters according to structural similarity of compounds. Representatives of every cluster were docked on a rigid structure model of a protein-target. In the second step, those clusters that contain identified hits were docked on a model of a protein-target. In the third step best docked molecules, with IC50 > 10um were sent to a refinement calculation. The refinement procedure provided a complete Free Energy Perturbation molecular dynamics run for a whole protein-ligand complex in aqueous environment, which takes into account protein flexibility. As a result 11 clusters of highly active compounds were identified.