Lead discovery

Assessment of the consistency of medicinal chemists in reviewing sets of compounds. Lajiness, M. S. et al. J. Med. Chem. 21 Aug 2004 (doi:10.1021/jm049740z)

Medicinal chemists are often asked to evaluate lists of compounds for their suitability as potential leads, but how consistent are the opinions of different medicinal chemists? To address this question, the authors performed an experiment in which a subset of 250 compounds rejected as unsuitable by a very experienced medicinal chemist were added to lists of ∼2,000 compounds. These combined lists were then evaluated by 13 other medicinal chemists, and, interestingly, it was found that they were not very consistent in the compounds that they rejected as undesirable.

High-throughput screening

Nonspecific enhancement of gene expression by compounds identified in high-throughput cell-based screening. Cunningham, S. C. et al. Biotechniques 37, 120–122 (2004)

Artefacts in high-throughput screening can be a major problem. Cunningham et al. investigated the ability of compounds to nonspecifically up- or down-regulate reporter plasmids in cell-based screening assays. Their results indicated that typical compound libraries can be expected to contain a group of compounds that nonspecifically modulate gene expression, which would be useful to take into account when performing such assays.

Biotechnology

DNA-templated organic synthesis and selection of a library of macrocycles. Gartner, Z. J. et al. Sciencexpress 19 Aug 2004 (doi:10.1126/science.1102629)

Evolution-based approaches can be powerful for creating molecular function, but can only be applied to molecules that can be translated from amplifiable information carriers; for example, the translation of DNA into proteins. Recent efforts have focused on extending the possibilities of such approaches to small molecules (for example, see p727 of the September issue). Gartner and colleagues describe an approach based on DNA-templated organic synthesis that allows the translation, selection and amplification of DNA libraries into synthetic small molecules.

Tuberculosis

Synthesis and biological evaluation of new inhibitors of UDP-Galf transferase — a key enzyme in M. tuberculosis cell wall biosynthesis. Cren, S. et al. Org. Biomol. Chem. 2, 2418–2420 (2004)

Cren et al. describe the first inhibitors of a key enzyme involved in the biosynthesis of D-galactans found in the cell wall of Mycobacterium tuberculosis: UDP-Galf transferase. These compounds could represent promising leads for the development of new antituberculosis drugs that lack serious side effects, because the main constituents of D-galactans are not found in mammalian metabolism.