Obesity

Activation of central melanocortin pathways by fenfluramine.Heisler, L. K. et al. Science 297, 609–611 (2002)

d-Fenfluramine (d-FEN) was once widely prescribed as an appetite suppressant, but was withdrawn owing to cardiac complications in a subset of patients. Heisler et al. show that d-FEN-induced anorexia requires activation of melanocortin pathways in the central nervous system, which have a well-established role in food intake. Their results provide a mechanistic explanation for the anorexic activity of d-FEN, and indicate that drugs that target these melanocortin pathways might prove to be effective anti-obesity treatments with fewer side effects.

Computational chemistry

Identification of potent and novel α4β1-antagonists using in silico screening.Singh, J. S. et al. J. Med. Chem. 45, 2988–2993 (2002)

The integrin α4β1 has a key role in the inflammatory response, and has been implicated in the pathology of diseases such as asthma, multiple sclerosis and rheumatoid arthritis. A potent and selective inhibitor for α4β1 based on a peptide sequence from the natural ligand for α4β1 had previously been identified, but its peptidic nature resulted in rapid clearance in animals. Singh et al. used a three-dimensional pharmacophore model of the peptidic inhibitor to search a chemical database for structures that satisfy the constraints of the model, and identified a potent non-peptidic inhibitor of α4β1, which showed encouraging activity in a sheep model of asthma.

High-throughput screening

Screening inhibitors of anthrax lethal factor.Tonello, F. et al. Nature 418, 386 (2002)

New and specific therapies to combat the potential threat of anthrax are urgently needed. Tonello et al. describe an assay for detecting inhibitors of lethal factor, a proteolytic enzyme that is one of the three components of anthrax toxin. The substrates for lethal factor that the authors created allow detection of proteolytic activity using visible-light or fluorescence detectors in a high-throughput format.

Lead identification

SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets.Swayze, E. E. et al. J. Med. Chem. 2002 Jul 27 (doi: 10.1021/jm0255466)

RNAs are attractive drug targets, but high-throughput screening against RNA targets has yielded active compounds at much lower rates than those usually observed for protein targets. Swayze et al. used mass spectrometry to determine structure–activity relationships for weak-binding 'motif' compounds, which were used to guide the linkage of these motifs into high-affinity ligands for a subdomain of bacterial 23S rRNA.