Volume 2 Issue 2, February 2006

The goal of high-throughput screening (HTS) from the perspective of the biologist is to identify a highly specific small molecule that can be used to inhibit a protein in its normal biological context. Although several useful small molecules have been identified with HTS, there are many challenges to be considered when contemplating a screen, especially by those unfamiliar with chemical biology.

What do organic synthesis, mechanistic enzymology, structural biology and glycoscience have in common? They all span chemistry and biology, benefit from and contribute to multidisciplinary approaches, and were up for discussion at a recent symposium in Dublin.

The report of a new class of potent and highly selective inhibitors of Bcr-abl highlights the potential for a truly leukemia-specific drug with no expected off-target activity. GNF-2, as a representative compound of this class, may have inspired the identification of a region of Bcr-abl that is amenable to drug design, just as imatinib did almost a decade ago.

DNA in the nucleus of mammalian cells is extensively associated with proteins. Potential anticancer agents can access, recognize and alkylate nucleosomal DNA, even at sites that seem completely occluded by association with histone proteins.

Modern single-molecule tools, when applied to enzymes, challenge fundamental concepts of catalysis by uncovering mechanistic pathways, intermediates and heterogeneities hidden in the ensemble average. It is thus reassuring that the Michaelis-Menten formalism, a pillar of enzymology, is upheld, if reinterpreted, even when visualizing single turnover events with a microscope focus.

Studies have linked the Fucα(1-2)Gal modification of neuronal glycoproteins to cognitive processes such as learning and memory. The identification of synapsins Ia and Ib as the main Fucα(1-2)Gal-bearing neuronal proteins not only suggests previously unknown molecular mechanisms of neuronal plasticity but also indicates the existence of previously unknown glycosylation pathways in neurons.