Optimizing the Sunitinib for cardio-toxicity and thyro-toxicity by scaffold hopping approach.

Sunitinib is a potent anti-cancer scaffold that acts as a VEGFR-2 inhibitor. Although the scaffold exhibits potent anti-cancer activity, it is cardiotoxic and also induces hypothyroidism. The current research aims to optimize the Sunitinib for cardio-toxicity and thyro-toxicity by scaffold hopping approach using the admetSAR server. The server has optimized the physico-chemical properties of Sunitinib, which were contributing to the cardiotoxicity and thyro-toxicity. The library of the optimized compounds was further screened by the molecular docking studies and results were validated by the MD simulation and DFT analysis for VEGFR-2 inhibition. Compounds 163 and 432 exhibited the highest affinity to VEGFR-2 receptor with minimal cardiotoxicity and thyro-toxicity. These two compounds could be the starting point for the further discovery of angiogenic inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-022-00125-1.