Docking and Cheminformatic Analysis of Protein-Ligand Interactions: Cytochromes P450 (2D6 and P450 CAM) and Estrogen Receptors from Human and Zebrafish

Chemists are inundated with vast amounts of raw data: spectral data, synthetic data, stereochemically complex registered chemical structures, SAR (Structure Activity Relationships) and pharmacological studies, and enormous arrays of data from HTS (High Throughput Screening) and combinatorial chemistry. Cheminformatic systems facilitate the collection, storage and manipulation of these data to provide useful information for driving the drug discovery and development process. Cheminformatics is the use of computer (hardware and software) and informational techniques, applied to a range of problems in the field of chemistry. Also known as chemoinformatics and chemical informatics, these techniques are used in pharmaceutical companies in the process of Drug Discovery (for chemical screening and analysis). New fields such as combinatorial chemistry or high throughput screening (HTS) are developing rapidilly and highlight a need for rapid evolution of chemical entities as potential candidates for development as new drugs. Since up to 70 % of drug candidates fail to proceed through clinic trials, due most of the time to unpredicted toxicity or side effects, it is highly desirable to eliminate such compounds as early in development as possible. Very often these properties become apparent only after considerable investment in and testing of the compounds in question has occurred. It is estimated that an improvement of as little as 12% in the identification rate of poor candidates could save large companies $270 million per year. Also, the average time it takes for a company to get a drug to market is almost fourteen years. Therefore, the speed with which a company passes through the various stages of the drug discovery process is critical to success. The pharmaceutical industry is constantly looking for new ways to reduce drug discovery time by identifying new targets and novel drugs to make the entire process more efficient and cost-effective. So rational drug design based on docking ligands into protein binding sites, combined with combinatorial chemistry, is one area in which tremendous advances are taking place. Such studies are the focus of this thesis..