Abstract 6693: Targeting oncogenic miR-135b in colorectal cancer: Computational modeling and small molecule screening for RNA-based therapy

Abstract Colorectal cancer ranks among the leading causes of cancer-related deaths globally. In this study, we identified miR-135b as a differentially expressed microRNA in colorectal cancer through an analysis of datasets from the Gene Expression Omnibus (GEO) database. Target genes associated with miR-135b were subsequently identified, and pathway and functional enrichment analyses were conducted to provide a deeper understanding of the underlying biological processes. We developed a de novo three-dimensional model of miR-135b's tertiary structure, targeting the Dicer cleavage site for small molecule inhibition. Dicer binds to the terminal loop region of the pre-miRNA and cleaves it to produce a double-stranded miRNA duplex. One strand of this duplex, the guide miRNA, is loaded into the RNA-induced silencing complex (RISC), which mediates miRNA-mRNA interactions, leading to post-transcriptional gene silencing. To identify potential inhibitors, molecular docking simulations were conducted using the ChemDiv miRNA-targeted small molecule library (∼20, 000 compounds). The top-scoring compounds were further explored by screening their commercial analogues in the ZINC library via SwissSimilarity. These analogues were docked at the Dicer cleavage site, and optimized docking scores were obtained. The highest scoring compounds were then subjected to all-atom molecular dynamics simulations, followed by post-simulation analysis to evaluate the dynamic interactions between miR-135b and the selected hit ligands. Citation Format: Berat Demir, Lalehan Oktay, Serdar Durdagi. Targeting oncogenic miR-135b in colorectal cancer: Computational modeling and small molecule screening for RNA-based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6693.