Drugs targeting microRNAs that regulate DNA damage sensing and repair mechanisms: A computational drug discovery approach

Abstract

DNA damage-sensing (DDS) and DNA damage-repair (DDR) mechanisms are essential for the fidelity of genetic information transmission. Failure to accomplish an effective DDS/DDR mechanism can lead to cell death or otherwise to cell transformation and cancer development. microRNAs (miRs) are short noncoding RNAs that primarily function as micromanagers of gene expression. Herein, we aimed to investigate the links between miRs and the translation of specific mRNAs encoding proteins involved in genomic DDS and DDR and to screen drugs that have high binding affinity to the selected miRs, which may serve as cancer therapeutics. To accomplish these aims, we used a variety of computational methods spanning data analysis, molecular modeling, and simulation tools (i.e., PyRx, Biopython, ViennaRNA, RNAComposer, AutoDock Vina, OpenBabel, PyMOL, Discovery Studio, MarvinSketch). The genes and miRNAs involved in the DDS and DDR mechanisms were retrieved from either the literature or various online databases (e.g., miRDB). miR data were further cleaned and prepared using scripts, and various libraries were used to obtain their 3-D structures. Genes interacting with miRs were enriched based on multiple database annotations using Enrichr KG. Then, we used docking analyses to virtually screen compounds to serve as ligands for the miRs. Finally, we generated gene-disease-miR-drug networks to study the linkages between the compounds and miR molecules under investigation. For the first time, we were able to identify five compounds that could be repurposed for downregulating miRs that are linked to inhibition of translation of mRNA involved in the DDS and DDR processes. The gathered candidate drugs can be useful for preventing cell transformation and cancer development.