Towards the discovery of drug-like RNA ligands?
Targeting RNA with small molecule drugs is an area of great potential for therapeutic treatment of infections and possibly genetic and autoimmune diseases. However, a mature set of precedents and established methodology is lacking. The physicochemical properties of RNA raise specific issues and obstacles to development, and contribute to explain the distinct characteristics of natural RNA ligands, including antibiotics. Yet, RNA-targeting strategies are being implemented to reinvigorate antibacterial discovery by using the ribosomal X-ray structures to modify known antibiotics. To exploit further these structures, we suggest the use of existing protein kinase-directed libraries of drug-like compounds to target the A-site of the bacterial ribosome, on the basis of a specific structural hypothesis.
Foloppe
Nicolas
N
Vernalis (R&D) Ltd., Granta Park, Abington, Cambridge, CB1 6GB, UK.
Matassova
Natalia
N
Aboul-Ela
Fareed
F
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012313:RNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D012329:RNA, Bacterial / Q000737:chemistry; D012335:RNA, Ribosomal / Q000737:chemistry; D022661:RNA, Untranslated / Q000737:chemistry; D012367:RNA, Viral / Q000737:chemistry; D012270:Ribosomes / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D022661:RNA, Untranslated; D012367:RNA, Viral; D012313:RNA