(Figure 3). Different conformational states during cellular activation, particularly in the presence of accessory proteins, may easily change a singe hydrogen bond or electrostatic attraction, changing affinity. Indeed, it must be pointed out that one additional hydrogen

bond between the compound and the target can change the affinity thirty-fold. This complexity may induce inadequate responses to predict therapeutic efficacy. As compound selection is the crucial issue, we have argued that, after preliminary screens in recombinant systems, and following exclusion of inappropriate Inhibitors,research,lifescience,medical Serotonin receptor drugs compounds (for metabolic or safety reasons), the selection of the final compound to proceed onto development should take place in pathophysiological models, and preferably, Inhibitors,research,lifescience,medical if breakthrough compounds are looked for, in novel pathophysiological models. However, this means a major investment in screening in animal models. In vivo screening Animal models are often the limiting factor in research (particularly Inhibitors,research,lifescience,medical for cognitive issues), and finding staff skilled in their handling is not easy. Previous drugs have been tested for in the established models, and the way to test, benzodiazepine anxiolytics is to use the classic anxiety screening models, defined by diazepam. However, novel

drugs working in new ways may need new models. Thus, compounds should be selected using a model of pathophysiological conditions. However, this needs skilled pharmacologists’ with an integrative vision of pathophysiology. How are new drugs discovered? New drugs may be discovered in very

many ways, but discovery nearly always involves tight Inhibitors,research,lifescience,medical collaborations between chemists and pharmacologists, who must identify the cellular and genetic factors important in pathophysiology, produce appropriate hypotheses, and design new test systems. Screening Inhibitors,research,lifescience,medical new molecules can be done in a number of ways. Target identification Ideally, the target should be the cause of a specific disease which can be targeted on a molecular level. There has been immense progress made in defining the receptor systems in the human genome, by analogy to existing 7-transmcmbrane receptors. This marks a unique moment in science, because many targets are becoming known. Lists of these receptors much have been produced (eg, ref 5). Furthermore, new targets remain to be discovered, and the existing targets are known to have many different forms (alternative splicing, messenger ribonucleic acid (mRNA) editing, single-nucleotide polymorphisms, etc) which may allow selective targeting of disease states. The bioinformatics industry provides an immensely powerful tool to scientists, and many of these data are in the public domain. Target validation A crucial issue is to validate the target, in animal and preferably in human models.