DrugPred_RNA-A Tool for Structure-Based Druggability Predictions for RNA Binding Sites.

Illimar Hugo Rekand,Ruth Brenk

doi:10.1021/acs.jcim.1c00155

Illimar Hugo Rekand, Ruth Brenk

Open Access

https://doi.org/10.1021/acs.jcim.1c00155

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Abstract

RNA is an emerging target for drug discovery. However, like for proteins, not all RNA binding sites are equally suited to be addressed with conventional drug-like ligands. To this end, we have developed the structure-based druggability predictor DrugPred_RNA to identify druggable RNA binding sites. Due to the paucity of annotated RNA binding sites, the predictor was trained on protein pockets, albeit using only descriptors that can be calculated for both RNA and protein binding sites. DrugPred_RNA performed well in discriminating druggable from less druggable binding sites for the protein set and delivered predictions for selected RNA binding sites that agreed with manual assignment. In addition, most drug-like ligands contained in an RNA test set were found in pockets predicted to be druggable, further adding confidence to the performance of DrugPred_RNA. The method is robust against conformational and sequence changes in the binding sites and can contribute to direct drug discovery efforts for RNA targets.

Highlights

The vast majority of targets for approved drugs are proteins.[1,2] in recent years, it has been increasingly realized that RNAs constitute promising drug targets as they play a key role in many biological processes, can fold into diverse 3D structures, and recognize small molecules.[3−6] By targeting RNA, the functions of currently undruggable proteinmediated pathways and the noncoding transcriptome can be modulated, and the size of the druggable genome can be increased considerably.[3]
Weak descriptors as judged by Shapley Additive Explanation (SHAP) values were removed until the predictive performance of the model was negatively affected
RNA is an emerging target for drug discovery.[3−6] like for proteins, not all RNA binding sites are suited to be addressed with conventional drug-like ligands

Summary

Introduction

The vast majority of targets for approved drugs are proteins.[1,2] in recent years, it has been increasingly realized that RNAs constitute promising drug targets as they play a key role in many biological processes, can fold into diverse 3D structures, and recognize small molecules.[3−6] By targeting RNA, the functions of currently undruggable proteinmediated pathways and the noncoding transcriptome can be modulated, and the size of the druggable genome can be increased considerably.[3]. This fact nicely illustrates the capability of RNA to make specific molecular interactions with a wide variety of functional groups and ligand surfaces.[3]

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