Contributions of protein structure-based drug design to cancer chemotherapy

Abstract

Protein structure-based drug design (SBDD) uses a knowledge of the molecular structure of a target macromolecule, normally obtained by x-ray crystallography, to design potent, selective inhibitors. This technique has played a major role in the design of a number of drugs that have progressed to clinical trials. Most of these compounds have been developed to treat viral diseases and cancer. In the antiviral area, drugs designed by SBDD have been developed for treatment of influenza and acquired immune deficiency syndrome. Three human immunodeficiency virus-I protease inhibitors that were designed at least partially using the x-ray crystal structure of the target enzyme are now approved for sale in the United States. In the anticancer field, no SBDD-designed drugs have yet progressed to market, but several experimental anticancer agents that were designed from a knowledge of the molecular structure of their target enzyme have advanced to clinical trials, of which at least one has shown clinical activity. The present article discusses the strengths and weaknesses of the SBDD approach, and shows its contributions to cancer chemotherapy by discussing rationally designed inhibitors of thymidylate synthase, purine nucleoside phosphorylase, glycinamide ribonucleotide formyltransferase, and matrix metalloproteases.