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

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.

Identification of two short peptide motifs from serine/arginine-rich protein ribonucleic acid recognition motif-1 domain acting as splicing regulators

“…Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. Small peptides, ideally less than 1 kDa have long been studied as efficient therapeutic drugs that can overcome many delivery issues ( Berdnikova et al, 2021 ). Besides their application as carriers, natural and synthetic peptides are resources for providing molecules that may interact with the spliceosome and/or alter molecular pathways ( Nancy, Nora & Rebeca, 2015 ).…”

Recent Advances in Photoswitchable Fluorescent and Colorimetric Probes

“…These molecules often contain functional groups such as azobenzene, capable of switching between trans and cis configurations under UV or visible light. Integrating these photoswitchable molecules into nucleic acids or designing them to bind specifically to nucleic acids allows for the reversible control of nucleic acid structure and function [ 232 , 233 , 234 , 235 ]. For example, light can be used to modulate the binding affinity of a photoswitchable molecule to a nucleic acid, thereby regulating gene expression, protein synthesis, or the structural conformation of nucleic acids.…”

Establishing the catalytic and regulatory mechanism of RNA‐based machineries

“…Thus, drug discovery campaigns aiming to identify and exploit druggable sites in RNA structures are highly challenging to tackle with traditional drug design approaches, as it is still unclear how to design small RNA‐binding molecules 170–174 . In this respect, MD simulations can significantly advance the field, by predicting the pose and affinity of ligands toward a RNA structure, 175 and by unraveling the ligand–RNA recognition processes 176,177 . We envisage in forthcoming years a prominent role of MD simulations in the development of novel pharmaceutical compounds targeting RNA and RNP‐machineries involved in disease development 178 …”

“…[170][171][172][173][174] In this respect, MD simulations can significantly advance the field, by predicting the pose and affinity of ligands toward a RNA structure, 175 and by unraveling the ligand-RNA recognition processes. 176,177 We envisage in forthcoming years a prominent role of MD simulations in the development of novel pharmaceutical compounds targeting RNA and RNPmachineries involved in disease development. 178 In conclusion, we believe that the synergic integration of computations and experiments will contribute to advancing our comprehension of the general and basic regulatory principles underlying RNA maturation.…”