Role and Perspective of Molecular Simulation-Based Investigation of RNA-Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding.

Daria V Berdnikova,Paolo Carloni,Giulia Rossetti,Sybille Krauß

doi:10.3390/molecules26113384

Daria V Berdnikova, Paolo Carloni + Show 2 more

Open Access

https://doi.org/10.3390/molecules26113384

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Abstract

Aberrant RNA–protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Thus, the use of molecular simulation may provide insight into aberrant molecular interactions in diseases and, from a drug design perspective, may allow for the employment of less wet lab resources than traditional in vitro compound screening approaches. With regard to basic research questions, molecular simulation can support the understanding of the exact molecular interaction and binding mode. Here, we focus on examples targeting RNA–protein complexes in neurodegenerative diseases and viral infections. These examples illustrate that the strategy is rather general and could be applied to different pharmacologically relevant approaches. We close this study by outlining one of these approaches, namely the light-controllable association of small molecules with RNA, as an emerging approach in RNA-targeting therapy.

Highlights

Thought to just act as the intermediate between DNA and protein synthesis, RNA is known to perform essential and diverse functions within cells
The CAG repeat expansion mutation in Huntington’s disease (HD) leads to an aberrant hairpin structure (Figure 2A) that is the basis of the non-physiological RNA–protein complexes involved in diverse cellular mechanisms including aberrant translation of neurotoxic polyglutamine protein
We show here how the combinations of advanced molecular simulations approaches and experiments led to the identification of RNA CAG binders able to counteract the pathogenic effects of aberrant RNA CAG hairpin–protein interactions in living cells

Summary

Introduction

Thought to just act as the intermediate between DNA and protein synthesis, RNA is known to perform essential and diverse functions within cells It forms part of the ribosome [1], the spliceosome [2], and other complex assemblies. Antisense oligonucleotides and synthetic RNAs that redirect the cellular RNA interference machinery or activate CRISPR-based systems have provided a proof of principle for drugs targeting RNA–protein complexes [8]. These approaches involve large, often highly charged molecules and present challenges of delivery with regard to crossing the blood–brain barrier, allergic reactions, and poor absorption [9]. In the conclusion of our review, as an example, we describe ligands involved in light-controllable RNA-targeting therapy

Targeting RNA Trinucleotide Repeat Expansions

RNA-Mediated Toxicity

MD Simulations of HTT RNA CAG with Small Molecules

Targeting HIV-1 TAR RNA Hairpin

Conclusions and Outlook