Virtual screening

Binding mode prediction of cytochrome P450 and thymidine kinase protein–ligand complexes by consideration of water and rescoring in automated docking. de Graff, C. et al. J. Med. Chem. 17 Feb 2005 (10.1021/jm049650u)

Despite the fact that water molecules can have an essential role in ligand–protein binding, most computational 'docking' methods for virtual ligand screening ignore water-mediated interactions between proteins and ligands. This study presents the first comprehensive evaluation of the effects of explicit active-site water molecules on molecular-docking-based binding-mode prediction with three widely used docking programs. Consideration of water molecules, and pooling and rescoring of all solutions generated by the docking programs, significantly improved the quality of prediction of the binding modes.

Cardiovascular disease

Circulating transcriptome reveals markers of atherosclerosis. Patino, W. D. et al. Proc. Natl Acad. Sci. USA 102, 3423–3428 (2005)

Circulating monocytes, which mediate inflammation in atherosclerosis, might serve as accessible reporters of disease. Patino et al. compared the in vivo transcriptomes of monocytes from patients with atherosclerosis and normal patients, and provide data that the FOS gene is a marker and mediator of atherosclerosis. Similar approaches examining the circulating transcriptome in other conditions might also be valuable.

Stroke

Recombinant activated factor VII for acute intracerebral hemorrhage. Mayer, S. A. et al. N. Engl. J. Med. 352, 777–785 (2005)

Early intervention with haemostatic therapy might improve outcomes after intracerebral haemorrhgage — the least treatable form of stroke. In this trial involving ∼400 patients, treatment with recombinant activated factor VII within 4 hours of the onset of intracerebral haemorrhgage was shown to limit the growth of the haemotoma, reduce mortality and improve functional outcomes at 90 days.

Kinases

Chemical genomic profiling to identify intracellular targets of a multiplex kinase inhibitor. Kung, C. et al. Proc. Natl Acad. Sci. USA 102, 3587–3592 (2005)

Identifying which kinases are targeted by protein kinase inhibitors is a key challenge in validating their use as therapeutic agents or chemical tools to probe biology. The authors describe a strategy to address this challenge that uses a direct comparison between microarray transcriptional signatures elicited by an inhibitor of unknown specificity and those elicited by highly specific pharmacological inhibition of engineered kinases, which they use to identify the targets of a cyclin-dependent kinase inhibitor of previously unknown specificity.