From in Silico to in Vitro Drug Discovery

Science's STKE  25 Apr 2006:
Vol. 2006, Issue 332, pp. tw140
DOI: 10.1126/stke.3322006tw140

Many currently available therapeutic drugs act by modulating signaling through G protein (heterotrimeric GTP-binding protein)-coupled receptors. The G protein βγ subunit transmits signals from G protein-coupled receptors to target proteins, and many crystal structures of such complexes have been solved. Bonacci et al. (see the Perspective by Tesmer) used a computer program to predict which chemical compounds would bind to the interaction site on the βγ subunits and obtained potent small-molecule inhibitors of protein-protein interactions. Furthermore, these molecules showed specificity for disrupting signaling-specific downstream targets, which suggests that such reagents might be both effective and relatively free of side effects.

T. M. Bonacci, J. L. Mathews, C. Yuan, D. M. Lehmann, S. Malik, D. Wu, J. L. Font, J. M. Bidlack, A. V. Smrcka, Differential targeting of Gβγ-subunit signaling with small molecules. Science 312, 443-446 (2006). [Abstract] [Full Text]

J. J. G. Tesmer, Hitting the hot spots of cell signaling cascades. Science 312, 377-378 (2006). [Summary] [Full Text]