Abstract
Rearranged during transfection (RET) is a tyrosine kinase oncogenic receptor, activated in several cancers including non-small-cell lung cancer (NSCLC). Multiple kinase inhibitors vandetanib and cabozantinib are commonly used in the treatment of RET-positive NSCLC. However, specificity, toxicity, and reduced efficacy limit the usage of multiple kinase inhibitors in targeting RET protein. Thus, in the present investigation, we aimed to figure out novel and potent candidates for the inhibition of RET protein using combined in silico and in vitro strategies. In the present study, screening of 11,808 compounds from the DrugBank repository was accomplished by different hypotheses such as pharmacophore, e-pharmacophore, and receptor cavity-based models in the initial stage. The results from the different hypotheses were then integrated to eliminate the false positive prediction. The inhibitory activities of the screened compounds were tested by the glide docking algorithm. Moreover, RF score, Tanimoto coefficient, prime-MM/GBSA, and density functional theory calculations were utilized to re-score the binding free energy of the docked complexes with high precision. This procedure resulted in three lead molecules, namely DB07194, DB03496, and DB11982, against the RET protein. The screened lead molecules together with reference compounds were then subjected to a long molecular dynamics simulation with a 200 ns time duration to validate the inhibitory activity. Further analysis of compounds using MM-PBSA and mutation studies resulted in the identification of potent compound DB07194. In essence, a cell viability assay with RET-specific lung cancer cell line LC-2/ad was also carried out to confirm the in vitro biological activity of the resultant compound, DB07194. Indeed, the results from our study conclude that DB07194 can be effectively translated for this new therapeutic purpose, in contrast to the properties for which it was originally designed and synthesized.
Highlights
IntroductionTargeted therapies using tailored inhibitors against oncogenic driver kinases have transformed the landscape of cancer management, including non-small-cell lung cancer (NSCLC) [1]
A pharmacophore is a collection of chemical features and spatial properties required for the ligand to interact with a macromolecular target and elicit a biological response [34]
The screened compounds were subjected to three tiers of docking such as high-throughput virtual screening (HTVS), standard precision (SP) and XP using pralsetinib (−7.79 kcal/mol) as a reference compound
Summary
Targeted therapies using tailored inhibitors against oncogenic driver kinases have transformed the landscape of cancer management, including non-small-cell lung cancer (NSCLC) [1]. First-generation inhibitors against oncogenic drivers such as gefitinib, erlotinib (EGFR mutations), and crizotinib (ALK rearrangement) have established a novel treatment paradigm for the use of targeted inhibitors in genetically defined NSCLC patients [2,3]. Despite the earlier success of these strategies, the emergence of acquired resistance against the therapy has become a significant challenge in developing selective and more potent next-generation inhibitors.
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