Novel resistance-free ret tyrosine kinase inhibitor discovery through dynamic structure-based pharmacophore and qsar modeling and virtual screening of ultra large ligand libraries

Gene fusion and point mutations cause to activate RET tyrosine kinase where the gene fusion is responsible for non-small cell lung cancer and papillary thyroid cancers and the point mutation on the RET proto-oncogene, which is the receptor tyrosine kinase, causes multiple endocrine neoplasia type 2A and 2B (MEN2A, MEN2B) and Familial medullary thyroid cancer. Furthermore, small molecules as inhibitors bind to the binding site of RET kinase domain to block their enzymatic activity. On the other hand, a single amino acid change on the RET kinase position can provide resistance to the tyrosine kinase inhibitors, so it is essential to find a compound with activity against RET mutants. So, we hypothesize that with in-silico E-pharmacophore modeling of molecular dynamics trajectories and predicting pIC50 values of small molecules from several libraries using QSAR models, we can discover new small molecules that can inhibit the activation of RET proto-oncogene and their signaling pathways, so it can stop the growth of tumor sizes with the lowest resistance to that inhibitor.