Lead Identification

Informative library design as an efficient strategy to identify and optimize leads: application to cyclin-dependent kinase 2 antagonists. Bradley, E. K. et al. J. Med. Chem. 46, 4360–4364 (2003).

The authors describe the application of a computational library-design strategy to the identification of cyclin-dependent kinase 2 (CDK2) antagonists, and show that it outperforms a lead-identification strategy commonly used in industry.

Importantly, the dataset of 17,550 compounds and corresponding CDK2 activities used in this retrospective study has been freely released, which should facilitate further analysis to expand on these initial comparisons.

Antiviral Drugs

PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Li, F. et al. Proc. Natl Acad. Sci. USA 22 Oct 2003 (doi: 10.1073/pnas.2234683100)

Anti-HIV therapies with new mechanisms of action are desirable as they might be more likely to be active against the growing proportion of virus strains that are resistant to all the main classes of current drugs. Li et al. characterized the anti-HIV drug candidate PA-457, and showed that it inhibits HIV-1 replication by a previously unidentified mechanism — disrupting virus maturation — thereby providing further opportunities for anti-HIV drug discovery.

High-Throughput Screening

A specific mechanism of non-specific inhibition. McGovern, S. L. et al. J. Med. Chem. 46, 4265–4272 (2003).

Previous research by McGovern, Shoichet and colleagues has shown that some 'promiscuous hitters' in high-throughput screening assays — compounds that inhibit many different enzymes and are therefore unlikely to be good starting points for drug discovery — form submicrometre aggregates. The authors now provide evidence that aggregates formed by promiscuous hitters reversibly sequester enzymes, resulting in apparent inhibition, and suggest a simple method to identify or reverse the action of aggregate-based inhibitors involving the addition of detergent.

Antibacterial Drugs

A new class of bacterial RNA polymerase inhibitor affects nucleotide addition. Artsimovitch, I. et al. Science 302, 650–654 (2003).

RNA polymerase (RNAP) is the central enzyme in gene expression. Artsimovitch and colleagues identified and characterized a new class of bacterial RNAP inhibitor that does not inhibit human RNAPII, which — in combination with available crystal structures of bacterial RNAPs — could form a promising basis for the rational design of drugs that specifically target the main classes of bacterial pathogens.