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

Noreen F. Rizvi, John P. Santa Maria, Ali Nahvi, Joel Klappenbach, Daniel J. Klein, Patrick J. Curran, Matthew P. Richards, Chad Chamberlin, Peter Saradjian, Julja Burchard, Rodrigo Aguilar, Jeannie T. Lee, Peter J. Dandliker, Graham F. Smith, Peter Kutchukian, Elliott B. Nickbarg

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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 (~50,000 compounds) and functionally annotated tool compounds (~5100 compounds). The set of RNA–small molecule interactions that was generated was compared with that for protein–small molecule interactions, and naïve 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 ~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.

Original languageEnglish
Pages (from-to)384-396
Number of pages13
JournalSLAS Discovery
Volume25
Issue number4
DOIs
Publication statusPublished - 1 Apr 2020
Externally publishedYes

Keywords

  • drug screening
  • drug target
  • mass spectrometry
  • noncoding RNA
  • RNA

ASJC Scopus subject areas

  • Biotechnology
  • Analytical Chemistry
  • Biochemistry
  • Molecular Medicine

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