Virtual Screening Of Specifie Insulin-Like Growth Factor1Receptor (IGF1R) Inhibitors

Insulin-like growth factor1receptor (IGF1R) is an attractive drug target for cancertherapy. In the area of anti-tumor-drug study and development, much attention has beenpaid to the discovery and optimization of IGF1R inhibitors, and some of them have gainedsuccess in the initial stage of clinical tests. Due to the high identical sequences whiledifferent bio-functions between IGF1R and IR (Insulin Receptor), discovery of IGF1Rspecific inhibitor has become a challenge. By far some research groups have been reportedsome specific IGF1R inhibitors, which are discovered by combining bio-chemical assayswith computer-aided technologies. It has made a good foundation for further studies onvirtual screening of IGF1R specific inhibitors. Virtual screening based lead identificationcould not only sharply shorten the time for drug development but also increase the hit-rateof bio-chemical assays, which in total decrease the cost. In this study, we established avirtual screening workflow to identify poteitial IGF1R inhibitors in a high speed, based onthe benchmark results of IGF1R and several kinase receptors with IGF1R-like structures.Wealso built a binding pose predicting workflow to scrutinize the differences between thebinding characteristics of ligand-IGF1R and ligand-IR complexes, through comprehensiveanalysis of the known complexes of IGF1R and IR with their crystal ligands. Variouseffective testing sets were built to confirm the ability of the two workflows. Furthermore,under the help of the two workflows,17of139,735compounds in the NCI (NationalCancer Institute) database were identified as potential specific inhibitors of IGF1R.Calculations of the potential of mean force (PMF) with GROMACS were furtherconducted for three of the identified compounds （ID351570,660826and649812）toassess their binding affinity differences towards IGF1R and IR. Finally,compound351570and649812were identified as the most potential IGF1R specific inhibitors. Results ofbio-chemical assays published by NCI confirmed that compound649812and660826iscapable of inhibiting several types of human tumor cells. The inhibitory activity of theseidentified ligands to IGF1R in vitro or in vivo will wait for further experimentalverification.