Antibacterial drugs

A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Charest, M. G. et al. Science 308, 395–398 (2005)

Many antibiotics are based on natural products, such as the tetracyclines. However, the complexity of natural product structures is a major obstacle to synthesizing novel derivatives with the aim of enhancing their usefulness as drugs. Charest et al. report a short and efficient route for synthesizing a range of tetracyline derivatives that could be studied as potential new candidates for combating the widespread problem of antibiotic resistance.

G-protein-coupled receptors

GPCR antitarget modeling: pharmacophore models for biogenic amine binding GPCRs to avoid GPCR-mediated side effects. Klabunde, T. & Evers, A. ChemBioChem 6, 876–889 (2005)

G-protein-coupled receptors (GPCRs) that bind biogenic amines such as dopamine, serotonin and adrenaline have proved to be excellent drug targets. However, the key role that such GPCRs have in cell signalling can pose a risk for new drug candidates that show 'side affinities' for them. The authors present pharmacophore models that can rationalize the affinity of numerous drug candidates for various key GPCRs that bind biogenic amines, which could be valuable in developing drugs with improved safety profiles.

Computational Chemistry

“ In situ cross-docking” to simultaneously address multiple targets. Sotriffer, C. A. & Dramburg, I. J. Med. Chem. 48, 3122–3125 (2005)

In standard 'docking' approaches for investigating ligand–protein interactions, separate calculations are needed for each protein target of interest, which is time-consuming, both in terms of computing time, and also with respect to set-up and analysis of multiple runs. Sotriffer and Dramburg present an approach in which multiple proteins can be addressed in a single docking run, which might help in more efficiently addressing issues such as selectivity and protein flexibility.

Alzheimer's disease

Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Ab42 production. Kukar, T. et al. Nature Med. 11, 545–550 (2005)

Increased production of the 42-amino-acid form of amyloid-β (Aβ42) has been linked to the development of Alzheimer's disease. Some commonly used painkillers have been shown to inhibit the production of Aβ42, but Kukar and colleagues now identify a number of compounds, including cyclooxygenase 2 (COX2)-selective agents such as celecoxib and the antilipidaemic agent fenofibrate, that raise Aβ42, which suggests that studies to investigate the effects of such agents on the pathogenesis of Alzheimer's disease are warranted.