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Abstract Introduction: Colon and/or rectal cancer together constitute colorectal cancer (CRC), the 2nd most lethal and the 3rd common cancer worldwide. Drug resistance to modern chemotherapies results in decreased therapeutic efficacy and CRC treatment failure. Herein, multi-layered strategies are used for a better identification of the newer therapeutics. Methodology: Different publicly available datasets were used for the identification of the differentially expressed genes (DEGs) between normal and CRC tissues. miRNAs, lncRNAs and small molecules interacting with those DEGs were mined from various databases. A complex network of interacting mRNA-miRNAs-lncRNAs-small molecules was created using the Cytoscape. Hub RNAs, significant modules and cliques were identified using Cytohubba and MClique plugins. The mRNAs from the top 30 cliques were analyzed by expression, oncoprint, survival and gene ontology. Polyphenols from the PhenolExplorer database were also assessed for their druggability and toxicity properties to finally obtain druggable polyphenols (DPs). A two-step molecular docking was done using PyRx for mRNAs from top 30 cliques and DPs and the top ten complexes were docked again using AutoDock. Molecular dynamics simulation (MDS) is performed for the best fit protein-proposed DP vs protein-known drug using GROMACS. Results: 1915 DEGs, 2609 miRNAs, 1411 lncRNAs and 8790 small molecules (other than selected DPs) interactions were considered for generating a comprehensive interaction network. The 27 mRNAs from the top 30 cliques were subjected to an array of analyses. NCAPD2, CDK4 and FASN were found to be involved in different stages of CRC. IRF2BPL, CMPK1, CCNF and UST were found as survival biomarkers, whereas FAT4 was found to be the only genetically altered mRNA. Functional enrichment supported the analysis revealing significant CRC-associated gene ontology as well as pathways. 56 DPs when docked with the DEGs, the two-step docking revealed NQO1-Episesaminol to be the best target-drug complex. Results of docking were comparable when MDS was performed for NOQ1•Episesaminol Vs NQO1•Doxorubicin (approved drug). Conclusion: In the current interaction network and MDS-based integrated analysis, significant druggable CRC biomarkers and their newer therapeutic solutions were identified. MDS reveals NQO1•Episesaminol as a potential target•drug combination for CRC. Citation Format: Sohini Chakraborty, Gaurav Sharma, Sricheta Karmakar, Prarthana Chatterjee, Saptarshi Sinha, Pradipta Ghosh, Satarupa Banerjee. Targeting NQO1 with Episesaminol: A new therapeutic option identified for colorectal cancer using integrated systems biology and structural biology-based approach abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4490.
Chakraborty et al. (Fri,) studied this question.