Computational Tools for Design of Selective Small Molecules Targeting RNA: From Small Molecule Microarrays to Chemical Similarity Searching

  • Matthew G. Costales
  • Jessica L. Childs-Disney
  • Matthew D. DisneyEmail author
Part of the Topics in Medicinal Chemistry book series (TMC, volume 27)


RNA is an important drug target, yet few lead compounds elicit their effects by acting on RNA outside of the bacterial ribosome. Herein, we describe various synergistic strategies to identify small molecules that target RNA and how computational approaches can be utilized for lead optimization. In particular, we describe the development of small molecule microarray approaches applied towards RNA and its application to identify small molecule binders and for the facile study of antibiotic resistance mechanisms for known or novel lead antibacterials. Additionally, a microarray-based library-versus-library screen, which probes millions of combinations, is described that identifies RNA motif binding partners preferred by small molecules. Lead compounds can be designed by searching for these privileged interactions in a disease-causing RNA. Computational chemistry can be used to optimize these compounds. For example, lead compounds that target the r(CCUG) repeats expansions that cause myotonic dystrophy type 2 (DM2) were lead optimized by using structure-based design. Specifically, the compounds were developed to allow an in situ click chemistry approach in which a disease-affected cell synthesizes its own drug on-site by using the disease-causing biomolecule as a cellular catalyst. In another lead optimization strategy, chemical similarity searching was employed to lead optimize small molecules that target the r(CUG) repeat expansion that causes myotonic dystrophy type 1 (DM1). These studies allowed for the identification of an in vivo active small molecule that targets r(CUG) and improves disease-associated defects. As more studies are completed to understand the role of RNA in disease biology, the number of potential RNA targets will increase. In order to leverage these important investigations to develop compounds that target RNA, approaches that allow one to identify and optimize small molecules for selectivity and potency must be carefully considered.


Chemical biology Drug design High throughput screening Nucleic acids RNA 


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Matthew G. Costales
    • 1
  • Jessica L. Childs-Disney
    • 1
  • Matthew D. Disney
    • 1
    Email author
  1. 1.Departments of Chemistry and NeuroscienceThe Scripps Research InstituteJupiterUSA

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