Discovery of drugs

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

Nowhere is the need for specificity so great as in trying to design therapies for the human brain. Here there are numerous receptors that affect our moods, sleep, alertness, memory, and coordination. Even though the importance of serotonin (5-hydroxytryptamine, 5-HT) had been known to neuroscientists for over 100 years, it wasn t until the discovery of drugs... 

For those interested in the discovery of drug candidates to attenuate SSAO/ VAP-1 activity there are two properties that need to be considered. First, as mentioned above, SSAO/VAP-1 exists as a membrane bound protein and a truncated version is found in the plasma [10,11]. Second, there is tremendous species variation which is revealed in a very large range of the second order rate constant V/K, using benzylamine as substrate, [22,23], and that inhibitor potencies vary widely according to the species [24,25]. Furthermore, within a single species specific activity varies from tissue to tissue [26]. 

Historically, the discovery of drugs acting at G-protein-coupled receptors (GPCRs) has been extremely successful with 50% of all recently launched drugs targeting... 

Vane, J.R., The discovery of drugs and animal research, in Animal Edq>erimentation and the Future of Medical Research, Dotting, J.H., Ed., Portland Press, London, 1992, chap. 6. 

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

After the discovery of drugs with antidepressant activity in the late 1950s, an intensive search was undertaken for pharmacological models that would provide an understanding of the therapeutic effects observed and at the same time assist in the development of other, still more effective and specific antidepressants. In pharmacological tests then available, the prototype imipramine showed sedative, antihistaminic and anticholinergic effects and thus did not differ fundamentally from other medicaments with no antidepressant activity, e.g. antihistamines. The following observations then led to a further step forward in the development of hypotheses ... 

Cowan-Jacob SW, Fendrich G, Floersheimer A et al. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr 2007 63(Pt l) 80-93. 

The importance of the search for new paradigms for biodiversity conservation and new approaches to the discovery of drugs from the rain forest have been described in several recent publications, as well as in the RFA referred to above, and need not be discussed further here. The reader interested in more information is referred to any of the recent publications in this area.1016... 

Isolation and chemical characterization of TA started in the early nineteenth century (e.g. hyoscyamine in 1833 scopolamine in 1881 cocaine in 1862 [1]) thus representing early examples of pharmacognosy, which denominates the discovery of drugs from medicinal plants, fungi, bacteria and marine organisms [1, 8],... 

Amaro RE, Schnaufer A, Interthal H et al (2008) Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei. Proc Natl Acad Sci USA 105 17278-17283. doi 10.1073/pnas.0805820105... 

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