Chimeric 3D model of EGFR and VEGFR-2 for the discovery of dual inhibitors

Dual inhibition of protein kinases has become an attractive approach to overcome resistance observed in cancer treatment. Therefore, there is a great effort to develop new methodologies to identify multitarget inhibitors that can be clinically useful, including the use of distinct computational methods in the screening of chemical libraries to identify multitargeted inhibitors. Based on the induced fit principle, we introduce here the concept of chimeric conformational models, in which we take advantage of homology modeling to propose an alternative protein conformation to those available in crystallographic databases, useful for the search of dual inhibitors. We applied this concept to build and validated a chimeric conformational models based on EGFR and VEGFR-2, two receptor protein kinases that have become key targets in cancer therapy. From a selected set of known inhibitors, we verified the chimeric conformational model capacity to identify dual EGFR/VEGFR-2 ligands. Next, we performed a virtual screening study with the LASSBio Chemical Library using the chimeric conformational model and selected EGFR and VEGFR-2 dual inhibitor candidates, which were used as a base for proposed structural modifications that, after synthesis, lead to a dual EGFR/VEGFR-2 inhibitor at the micromolar level.