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The increasing awareness of the essential role of RNA in controlling viral replication and in bacterial protein synthesis emphasizes the potential of ribonucleoproteins as targets for developing new antibacterial and antiviral drugs. RNA forms well defined three-dimensional structures with clefts and binding pockets reminiscent of the active sites of proteins. Furthermore, it precedes proteins in the translation pathway; inhibiting the function of a single RNA molecule would result in inhibition of multiple proteins. Thus, small molecules that bind RNA specifically would combine the advantages of antisense and RNAi strategies with the much more favorable medicinal chemistry of small-molecule therapeutics. The discovery of small-molecule inhibitors of RNA with attractive pharmacological potential would be facilitated if we had available effective computational tools of structure-based drug design. Here, we systematically test automated docking tools developed for proteins using existing three-dimensional structures of RNA−small molecule complexes. The results show that the native structures can generally be reproduced to within 2.5 Å more than 50−60% of the time. For more than half of the test complexes, the native ligand ranked among the top 10% compounds in a database-scoring test. Through this work, we provide parameters for the validated application of automated docking tools to the discovery of new inhibitors of RNA function.

Researchers' increasing awareness of the essential role played by RNA in many biological processes and in the progression of disease makes the discovery of new RNA targets an emerging field in drug discovery. Since most existing pharmacologically active compounds bind proteins, RNA provides nearly untapped opportunities for pharmacological development. The elucidation of the structure of the ribosome and other cellular and viral RNA motifs creates the opportunity for discovering new drug-like compounds that inhibit RNA function. However, further advances in understanding the chemistry and structure of RNA recognition are needed before these promises are fulfilled.

Drug-like molecules that bind RNA with sequence selectivity would provide valuable tools to elucidate gene expression pathways and new avenues to the treatment of degenerative and chronic conditions. Efforts at discovering such agents have been hampered, until recently, by the limited knowledge of RNA recognition principles. Several recent structures of aminoglycoside-RNA complexes have begun to reveal the structural basis for RNA-drug recognition. However, the absence of suitable chemical scaffolds known to bind the RNA major groove, where specificity could be provided by the diversity of functional groups exposed on the RNA bases, has represented a major obstacle. Here we report an investigation of the structural basis for recognition of an RNA stem-loop by neomycin, a naturally occurring aminoglycoside antibiotic. We found that neomycin binds the RNA stem-loop that regulates alternative splicing of exon 10 within the gene coding for human tau protein. Mutations within this splicing regulatory element destabilise the RNA structure and cause frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), an autosomal dominant condition leading to neurodegeneration and death. The three-dimensional structure of the RNA-neomycin complex shows interaction of the drug in the major groove of the short RNA duplex, where familial mutations cluster. Analysis of the structure shows how aminoglycosides and related drugs bind to the RNA major groove, adding to our understanding of the principles of drug-RNA recognition.

N,N-Dimethyltetradecylamine N-oxide (DTAO) is an appropriate surfactant to form micelles able to host the iron(iii) meso-tetrakis(2,6-dichlorophenyl)porphyrin [Fe(iii)(TDCPP)]. The so obtained microheterogeneous catalyst can induce biomimetic redox processes on organic substrates in aqueous medium, using sunlight and oxygen as clean reagents. The primary photochemical process consists in the photoinduced reduction of Fe(iii) to Fe(ii) with the contemporaneous oxidation of the axial ligand to radical species. The micelle environment may control some main parameters affecting the reactivity of these intermediates and, therefore, the chemoselectivity of the hydrocarbon oxidation processes. In contrast to what is observed in homogeneous organic solution, both cyclohexene and cyclooctene can be oxidised to the corresponding epoxides, with a selectivity higher than 90% in the case of cyclooctene. On the other hand, the main oxidation product of cyclohexene is cyclohex-2-en-1-one as expected in a hydrophobic micellar environment. The Fe(iii)(TDCPP)/DTAO photocatalyst is very promising also in view of obtaining catalytic systems capable of converting small amounts of toxic halogenated alkanes present in water into less dangerous products. In particular, CCl₄ can be reduced by ethanol or cyclohexanol with high quantum yields (>10⁻¹), with good conversion (ca. 75%) and turnover values (>1500).

The photochemical behaviour of IrCl62−has been investigated in acid solutions both in the presence and absence of Cl−ions. The results show that the complex is little photosensitive and that the nature and the quantum yield of its photoreactions depend on the type of excited state reached upon irradiation. Irradiation with 254-nm light (π → egligand-to-metal charge transfer transitions) causes two parallel photoreactions, yielding IrCl5(H2O)2−and IrCl5(H2O)−; the quantum yields of the two processes (but nottheir sum) depend on Cl−concentration, the formation of IrCl5(H2O)2−being favoured by the increase of [Cl−]. Irradiation with 313- or 365-nm light (which presumably correspond to t2g→ egligand field transitions) yields IrCl5(H2O)−in the absence of Cl−and IrCl63−in 1.2 F Cl−. Finally, irradiation with 433- or 495-nm light (π → t2gligand-to-metal charge transfer transitions) does not cause any appreciable reaction. As far as the irradiation at 254 nm is concerned, a photolysis mechanism is proposed which accounts for the detailed experimental results.