Our ultimate goal is to facilitate the development of RNA-directed therapies. RNA molecules participate as key players in many biological processes and adopt complex architectures that are required for functional integrity. The development of ligands that bind specifically to RNA folds opens exciting new ways to expand greatly the existing repertoire of protein-targeted therapeutics. Towards this objective, we focus on three areas of research:
Structure Determination of RNA Targets and RNA-Ligand Complexes
We use X-ray crystallography to investigate the three-dimensional architecture of RNA targets and their complexes with small molecules of both natural and synthetic origin. Our main interest is in proven and potential targets for therapeutic intervention, including bacterial ribosomal RNAs as well as structured regions of viral and cellular messenger RNAs.
Computational Chemistry of RNA-Ligand Interaction
Structural information from crystallography and NMR, along with data from biochemical experiments are combined as a basis to investigate in silico the molecular recognition of RNA. Our goal is to develop computational methods for ligand docking to RNA. A second objective is to use chemoinformatics approaches to analyze known RNA-binding small molecules from natural product sources. We want to develop rules that define RNA-“friendly” ligands, which will ultimately be applied to the design of novel synthetic ligands.
Design and Discovery of New Ligands for RNA Targets
Structure-based ligand design will be combined with chemoinformatics approaches to compose libraries of small molecules for screening against RNA targets. The libraries will be comprised of 1) small molecules that are selected from commercially available synthetic and natural sources by applying rules for RNA-“friendly” ligands, 2) compounds obtained from natural products by semi-synthetic modification, and 3) fully synthetic designed RNA-“friendly” ligands. The libraries are being tested in binding and functional assays that we develop in our laboratory.
