Design and identification of novel drug candidates targeting RET: Accurate drug affinity estimation using funnel metadynamics.

Rearranged during Transfection (RET) belongs to the family of receptor tyrosine kinases (RTK), which plays a vital role in cell growth and differentiation. Mutations in RTK can lead to the upregulation of various cancer cells. Although several drugs have been approved, their efficacy remains limited due to mutations in RET-RTK, which contributing to resistance against TK inhibitors. Hence, identifying novel inhibitors and gaining a comprehensive understanding of drug resistance mechanisms are crucial for developing more effective targeted therapies. An accurate estimation of receptor-ligand binding free energy remains a key goal in computer-aided drug design and development strategies. In this study, we design several anilinoquinazoline derivatives and identify potent inhibitors by employing computational approaches. We identified derivatives V2, V5, and G5, which exhibited greater binding affinity and resistance against the wild and mutant proteins compared to the reference drug vandetanib. The calculated absolute binding energy between a wild-type protein and vandetanib (-5.95 ± 2.1 kcal mol), obtained through funnel-metadynamics simulations, is consistent with the experimental value (-8.75 kcal mol). The potent derivative V2 displays a strong binding affinity with RET-wild type (-7.2 ± 2.2 kcal mol), suggesting that it could be a promising inhibitor of RET functionality.