PubMed1993
Although much has been written in recent years about rational drug design, no drug has been designed de novo, that is, without using a natural substrate or inhibitor or screening lead as a starting point. Instead, as we have seen, medicinal chemists continue to depend upon serendipitous discovery of novel biological activities and novel chemical entities for structures on which to begin work. What rational drug design really means at present is rational drug discovery and rational optimization. These result from the application of modern structural and mechanistic biochemistry, and good synthetic chemistry, to obtain structures with the desired spectrum of biological activities. Traditionally, lead compounds were discovered in plant and animal extracts, and more recently in microorganisms and chemical libraries. These traditional approaches continue, but are augmented by advances in molecular biology, which now provide pure proteins in quantity for screening and structure determination, as well as for characterization by modern biophysical methods. Remarkably, x-ray and NMR methods can now provide the most important information needed to design new drugs, that is, the conformations of ligands bound to target proteins. Approaches to identifying possible ligands based only on the knowledge of the enzyme active site are being developed. Some of these, such as CAVEAT, have been recently reviewed. In spite of these impressive gains, de novo design of new drugs will not be achieved until we learn how to logically build specific inhibitors of a target enzyme knowing only the protein sequence of the enzyme or the amino acid sequence of the messenger substances. We have a long way to go, because by this very rigorous definition, even the successful design of a new nonpeptide drug beginning with enzyme-ligand NMR or x-ray structure constitutes rational optimization. However, as this article has illustrated, we have made great progress. Some of the current and futuristic approaches to drug design are shown in Fig. 8. Development of useful enzyme inhibitors, designed by knowing the enzyme catalytic mechanism or discovered by screening for natural inhibitors, is a very successful rational method. Discovery of receptor antagonists by screening protocols is also productive.(ABSTRACT TRUNCATED AT 400 WORDS)