Pharmacogenomics and Drug Design

Abstract

The Human Genome Project is largely complete, so the problem facing scientists is how to maximize the use of the newly acquired data for improving health care. It is estimated that the number of therapeutic targets available for drug discovery will increase from the current number of 600 to 1000 to perhaps as many as 5000 to 10 000. In addition to the challenges that this number provides to the pharmaceutical industry, there is the issue of sequence variation through single nucleotide polymorphisms (SNPs), some of which may impact upon the way that the body handles drug treatment. This may be due to a direct effect on the binding site of the protein target through nonconservative alterations of the amino acid sequence, or else through indirect effects on drug metabolizing enzymes. In order to meet these challenges, the marriage of structural proteomics and computer-aided small molecule design will provide opportunities for creating new molecules in silico; these may be designed to bind to selected pharmacogenetic variants of a protein in order to overcome the nonresponsiveness of certain patient groups to a particular medicine. The basic aspects of these technologies, and their applicability to selected targets showing structural variation, form the basis of this chapter.