Docking and Molecular Dynamics Simulation-Based Analysis of Advanced Small-Molecule Kinase Inhibitors Identified pre-let-7 miRNA Binders.

Abstract

RNAs play crucial roles in various cellular actions, and the uncontrolled expression or improper folding of RNAs is a cause of many diseases. Certain oncogenic phenotypes stem from the overexpression of regulatory microRNAs that contain secondary structural elements. Thus, targeting disease-related microRNAs with small molecules is a potential anticancer strategy that has attracted growing interest. To probe the RNA-binding chemical space held in advanced small-molecule therapeutics, we screened the 78 FDA-approved small-molecule kinase inhibitors (SMKIs) for their binding affinity with pre-let-7 miRNA via a combination of computational methods and biophysical measurement. The best-ranked SMKIs based on docking scores were subjected to molecular dynamics (MD) simulation studies. Collectively, it provided reliable information on the binding affinity for the top-performed SMKI in the formation of SMKI-miRNA complexes with pre-let-7. Furthermore, the identification of the predicted most promising SMKI-miRNA interactions was validated by microscale thermophoresis. This study highlighted the necessity to characterize the biological targets of SMKIs, many of which are FDA-approved cancer agents, at the transcriptomic level with RNAs. The study also illustrates the possibility that the interaction with RNA targets may contribute to the observed biological and clinical performance of these approved SMKIs.