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

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Sunitinib is a potent anti-cancer agent targeting VEGFR-2.
• However, Sunitinib exhibits significant cardiotoxicity and hypothyroidism.
• Optimizing Sunitinib's safety profile is crucial for therapeutic development.

Purpose of the Study:

• To optimize Sunitinib's structure for reduced cardiotoxicity and thyro-toxicity using scaffold hopping.
• To identify novel VEGFR-2 inhibitors with improved safety profiles.

Main Methods:

• Scaffold hopping approach utilizing the admetSAR server for property optimization.
• Molecular docking, molecular dynamics (MD) simulations, and Density Functional Theory (DFT) analyses for VEGFR-2 inhibition screening.
• In silico evaluation of cardiotoxicity and thyro-toxicity.

Main Results:

• The admetSAR server successfully optimized physico-chemical properties contributing to Sunitinib's toxicity.
• Compounds 163 and 432 demonstrated high binding affinity to the VEGFR-2 receptor.
• These optimized compounds exhibited minimal predicted cardiotoxicity and thyro-toxicity.

Conclusions:

• Compounds 163 and 432 represent promising lead candidates for developing safer anti-angiogenic inhibitors.
• Scaffold hopping and computational methods are effective for optimizing drug safety and efficacy.
• Further research into these compounds could lead to novel cancer therapeutics.