Discovery of RET Inhibitors Targeting the V804M Mutation for Cancer Therapy Based on Molecular Modeling, Molecular Docking, and Molecular Dynamics Simulations

Abstract Aberrant activation of RET kinase is closely associated with the development of a variety of tumors. In particular, the V804M mutation, as a gatekeeper mutation of RET kinase, has been associated with drug resistance in tumors, and therefore, there is a need to develop RET inhibitors that specifically target the V804M mutation. In this study, we aimed to develop RET inhibitors with higher activity targeting the V804M mutation. 49 compounds based on phenylacetamide scaffolds with inhibitory effects on the V804M mutation were used as a dataset, and CoMFA, CoMSIA, Topomer CoMFA, and HQSAR models were developed to analyze the conformational relationships in depth by using 2D/3D‐QSAR technology. The adenosine binding site of the RET tyrosine kinase structural domain (PDB ID: 4CKJ) was investigated, and the key structural residues closely related to the biological activities were identified. Molecular dynamics simulations further revealed strong interactions between the new compounds and the receptor proteins and demonstrated stable binding conformations using free energy landscape mapping. Free energy calculations verified the stability of these conformations. ADMET calculations predicted the biopharmaceutical properties of the drug in vivo, which is important for the development of RET inhibitors targeting the V804M mutation for the treatment of relevant tumors.