It has been stated that integrated systems yield data that emerge from a ‘black box’ (i.e. not all of the physiological steps are understood), and although this poses no particular problems for pharmacologists who negate this apparent handicap through null techniques, it has been cited as a shortcoming of discovery as it entered the ‘genomic age’. Over the past 20 years recombinant techniques have been applied to discovery in attempts to remove this perceived problem and explicitly determine simple parameters for drug activity. This approach is based on the idea that the simple measures of direct activity on gene products can be used to predict drug action in much more complex systems to provide a more accurate prediction of therapeutic drug activity. In general, this endeavor has met with mixed success  leading to renewed interest in phenotypic complete systems for discovery. One of the main reasons for this change in opinion is the finding that, although recombinant systems can be simple, they can also differ significantly from natural systems and certainly represent only a window into the complete process of drug–organ interaction.
In view of the mixed success of recombinant pharmacology in discovery and also in light of the tremendous advances made in the design and implementation of phenotypic pharmacologic assays with label-free techniques [2–4], pharmacologic testing of new molecules on cell culture systems remain an extremely attractive option for discovery. The main disadvantage of previous whole systems as used in discovery is that the tissue source was animal tissue; this necessitated navigating the obvious hurdles of species difference. The need to deal with species difference is now obviated by the ability to test human cells.
The observation of drug effect on complete cellular systems in real time offers advantages in that multiplex signaling systems can be decoded through the use of real time kinetics [5–6]. However, there is another advantage to applying label-free technology to the analysis of drug responses from seven transmembrane receptors (7TMRs). It is now known that ligands do not necessarily cause receptors to interact with all cellular signaling pathways in a uniform fashion; thus, many ligands are ‘biased’ to aim receptor stimulus to selected signaling pathways . Under these circumstances, the relative stoichiometry of receptors and cellular signaling components can define drug profiles making it extremely difficult to determine meaningful indices of activity in all but the exact cell type targeted for therapy. Label-free technology can be extremely valuable in this biased signaling world in two ways. Firstly, biased ligands are predicted to yield variable potency ratios in different cells types for end organ response thus label-free assays can be an excellent method to ‘detect biased ligands’ (those that stabilize unique receptor active state conformations) [8,9]. Second, label-free assays may offer the most concrete hope for in vitro testing of drugs in human therapeutically relevant cell lines to identify useful phenotypic responses . In general, the propitious union of advanced label-free assay technology with the appreciation of newly discovered complexity in drug-receptor signaling has resulted in an exciting time for pharmacology and drug discovery. It will be equally exciting to see if these new technologies uncover molecular patterns of activity that translate into valuable clinical phenotypic profiles.
In this issue of Drug Discovery Today, Editor’s Choice, I have highlighted four recent papers that consider label-free in drug discovery. The papers featured are all available as free downloads.
Beginning his career as a synthetic chemist, Terry Kenakin received a Ph.D. in Pharmacology at the University of Alberta, Edmonton Canada. After a post-doctoral Fellowship at University College London, U.K., he joined Burroughs-Wellcome as an associate Scientist. From there he continued working in drug discovery at Glaxo Inc., GlaxoWellcome and finally GlaxoSmithKline. Leaving his position as a Director at GlaxoSmithKline Research and Development laboratories at Research Triangle Park, N.C. USA, Dr. Kenakin is now a professor in the Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill. At present he is engaged in studies aimed at the optimal design of drug activity assays systems, the discovery and testing of allosteric molecules for therapeutic application and the quantitative modeling of drug effects. In addition, he is Director of the Pharmacology curriculum at the UNC School of Medicine. He is a member of numerous editorial boards as well as co-editor in Chief of the Journal of Receptors and Signal Transduction and Editor in Chief of Current Opinion in Pharmacology. He has authored numerous articles and has written nine books on Pharmacology.
1. Williams, M. (2007) Enabling technologies in drug discovery: the technical and cultural integration of the new with the old. In: Comprehensive Medicinal Chemistry II, pp. 265–287, Elsevier Science
2. Cooper, M.A. (2006) Non-optical screening platforms: the next wave in label-free screening? Drug Discov. Today 11, 1068–1074
3. Fang, Y. (2010) Label-free receptor assays. Drug Discov Today 7, E5–E11
4. Cooper, M.A. (2006) Optical biosensors: where next and how soon? Drug Discov. Today 11, 1061–1067
5. Schröder, R. et al. (2010) Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements. Nat. Biotechnol. 28, 943–949
6. Stallaert, W et al. (2012) Impedance responses reveal b2-adrenergic receptor signaling pluridimensionality and allow classification of ligands with distinct signaling profiles. PLoS One 7, E29420
7. Kenakin, T.P. (2010) Perspectives in pharmacology: functional selectivity and biased receptor signaling. J. Pharmacol. Exp. Ther. 336, 296–302
8. Peters, M.F. and Scott, C.W. (2009) Evaluating cellular impedance assays for detection of GPCR pleiotropic signaling and functional selectivity. J. Biomol. Screen. 14, 246–255
9. Kenakin, T.P. (2010) A holistic view of GPCR signaling. Nat. Biotechnol. 28,928–929
10. Scott, C.W. (2010) Labeal-free whole-cell assays: expanding the scope of GPCR screening. Drug Discov. Today 15, 704–716