Structure-based discovery of ligands targeted to the RNA double helix.
Ligands capable of specific recognition of RNA structures are of interest in terms of the principles of molecular recognition as well as potential chemotherapeutic applications. We have approached the problem of identifying small molecules with binding specificity for the RNA double helix through application of the DOCK program [Kuntz, I. D., Meng, E. C., and Shoichet, B. K. (1994) Acc. Chem. Res. 27, 117-123], a structure-based method for drug discovery. A series of lead compounds was generated through a database search for ligands with shape complementarity to the RNA deep major groove. Compounds were then evaluated with regard to their fit into the minor groove of B DNA. Those compounds predicted to have an optimal fit to the RNA groove and strong discrimination against DNA were examined experimentally. Of the 11 compounds tested, 3, all aminoglycosides, exhibited pronounced stabilization of RNA duplexes against thermal denaturation with only marginal effects on DNA duplexes. One compound, lividomycin, was examined further, and shown to facilitate the ethanol-induced B to A transition in calf thymus DNA. Fluorine NMR solvent isotope shift measurements on RNA duplexes containing 5-fluorouracil provided evidence that lividomycin binds in the RNA major groove. Taken together, these results indicate that lividomycin recognizes the general features of the A conformation of nucleic acids through deep groove binding, confirming the predictions of our DOCK analysis. This approach may be of general utility for identifying ligands possessing specificity for additional RNA structures as well as other nucleic acid structural motifs.
Chen
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Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94143-0446, USA.
Shafer
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Kuntz
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ID
D000617:Aminoglycosides / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002942:Circular Dichroism; D003198:Computer Simulation; D007612:Kanamycin / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009355:Neomycin / Q000737:chemistry; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D010303:Paromomycin / Q000031:analogs & derivatives / Q000737:chemistry; D011063:Poly A-U / Q000737:chemistry; D012330:RNA, Double-Stranded / Q000737:chemistry*; D012984:Software; D017186:Titrimetry
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D008024:Ligands; D012330:RNA, Double-Stranded; D011063:Poly A-U; D007612:Kanamycin; D010303:Paromomycin; C100306:lividomycin; D009355:Neomycin