4.1 Article

Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space

Journal

SLAS DISCOVERY
Volume 25, Issue 4, Pages 384-396

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1177/2472555219885373

Keywords

RNA; noncoding RNA; drug screening; drug target; mass spectrometry

Funding

  1. Merck MINt award
  2. Pew Latin American Fellowship
  3. Merck Co., Inc.

Ask authors/readers for more resources

Although the potential value of RNA as a target for new small molecule therapeutics is becoming increasingly credible, the physicochemical properties required for small molecules to selectively bind to RNA remain relatively unexplored. To investigate the druggability of RNAs with small molecules, we have employed affinity mass spectrometry, using the Automated Ligand Identification System (ALIS), to screen 42 RNAs from a variety of RNA classes, each against an array of chemically diverse drug-like small molecules (similar to 50,000 compounds) and functionally annotated tool compounds (similar to 5100 compounds). The set of RNA-small molecule interactions that was generated was compared with that for protein-small molecule interactions, and naive Bayesian models were constructed to determine the types of specific chemical properties that bias small molecules toward binding to RNA. This set of RNA-selective chemical features was then used to build an RNA-focused set of similar to 3800 small molecules that demonstrated increased propensity toward binding the RNA target set. In addition, the data provide an overview of the specific physicochemical properties that help to enable binding to potential RNA targets. This work has increased the understanding of the chemical properties that are involved in small molecule binding to RNA, and the methodology used here is generally applicable to RNA-focused drug discovery efforts.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.1
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available