Silencing with precision: In silico strategies for antisense oligonucleotide engineering

Therapeutics based on nucleic acids are emerging as a transformative drug class in the era of personalized medicine. They include antisense oligonucleotides (ASOs), aptamers, small interfering RNAs (siRNAs), small activating RNAs (saRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), in addition to messenger RNAs (mRNAs). ASOs are short synthetic molecules of nucleic acids designed to bind to specific RNA molecules to allow for precise modulation of gene expression in a personalized medicine context. This review will summarize the state of the art in in silico tools and methods that are used for the design, 3D structural prediction, molecular docking, and simulation of ASOs, including their applications and limitations. By leveraging these computational approaches, the review will provide in silico methodologies toward improved specificity and efficacy of ASO therapeutics. These methodologies can enhance understanding of biological mechanisms of ASOs to allow for improved accuracy and efficacy of ASOs in the clinic while also providing new pathways toward the development of targeted therapies.