Some of the most exciting parts of work in the pharmaceutical industry are the steps leading up to drug discovery. This process can be oversimplified by describing it as a screening campaign involving the systematic testing of many compounds in a test relevant to a given pathology. This naïve description takes place without taking into consideration the numerous key steps that led up to the screening or the steps that might follow. The present chapter describes this whole process as it was conducted in our company during our early drug discovery activities. First, the purpose of the procedures is described and rationalized. Next follows a series of mostly published examples from our own work illustrating the various steps of the process from cloning to biophysics, including expression systems and membrane-bound protein purifications. We believe that what is described here presents an example of how pharmaceutical industry research can organize its platform(s) when the goal is to find and qualify a new preclinical drug candidate using cutting-edge technologies and a lot of hard work.
Part of the book: Drug Discovery
Melatonin actions are so numerous that a naive reader might become suspicious at such wonders. In a systematic way, we would like to summarize the various approaches that led to what is scientifically sounded in terms of molecular pharmacology: where and how melatonin is acting as a molecule, what can be its action as an antioxidant per se, and its side effects at a molecular level not as a drug or in vivo. Finally, the nature of the relationship between melatonin and mitochondria should be decrypted as well. The road we took from 1987 up to now, and particularly after 1995, will be mentioned with special considerations to the receptors from various species and our goals beyond that; the synthesis and catabolism of melatonin and their link to other enzymes; the discovery of the MT3 binding sites, and what’s left to understand on this particularly interesting target; and the search for agonists that occulted part of the potential discovery of true and potent antagonists, a situation quite unique among the G-protein-coupled receptors.
Part of the book: Melatonin