Rearranged during transfection (RET) tyrosine kinase is a transmembrane receptor tyrosine kinase regulating vital aspects of cellular proliferation, differentiation, and survival. An outstanding challenge in designing protein kinase inhibitors is due to the development of drug resistance. The "gain of function" mutations in the RET gate-keeper residue, Val804, confers resistance to the majority of known RET inhibitors, including vandetanib. To curtail this resistance, researchers developed selpercatinib (LOXO-292) against the RET gate-keeper mutant forms - V804M and V804L. In the present in silico investigation, a receptor-ligand pharmacophore model was generated to identify small molecule inhibitors effective for wild-type (WT) as well as mutant RET kinase variants. The generated model was employed to screen 144 766 natural products (NPs) available in the ZINC database and the retrieved NPs were filtered for their drug-likeness. The resulting 2696 drug-like NPs were subjected to molecular docking with the RET WT kinase domain and a total of 27 molecules displayed better dock scores than the reference inhibitors - vandetanib and selpercatinib. From 27 NPs, an aggregate of 12 compounds demonstrated better binding free energy (BFE) scores than the reference inhibitors, towards RET. Thus, the 12 NPs were also subjected to docking, simulation, and BFE estimation towards the constructed gate-keeper RET mutant structures. The BFE calculations revealed 3 hits with better BFE scores than the reference inhibitors towards WT, V804M, and V804L RET variants. Thus, the scaffolds of hit compounds presented in this study could act as potent RET inhibitors and further provide insights for drug optimization targeting aberrant activation of RET signaling, specifically the mutation of gate-keeper residue - Val804.
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