History of Drug Discovery

Abstract

Abstract Until the nineteenth century, natural extracts from the natural world were the only source of medicines. In the nineteenth century, experimental procedures were developed that were used to purify active principles from these extracts. The first of the semisynthetic analogues were also prepared during the nineteenth century. Towards the end of the century, purely synthetic agents were being prepared and organic synthesis became increasingly important throughout the twentieth century in preparing novel agents. The discovery of penicillin from a fungus sparked a postwar search for other antibiotics, and for lead compounds that were useful in other areas of medicine. In more recent years, advances in genomics and proteomics identified numerous potential drug targets, which initiated the development of automated synthetic methods in order to meet the demand for novel lead compounds. The principles of drug design have evolved over the last century, aided significantly by the development of X‐ray crystallography and computer‐based molecular modelling. Key Concepts: Up until the nineteenth century, the only medicinal therapies available were minerals or crude extracts obtained from natural sources such as plants, herbs and animals. From the nineteenth century, purification methods have been used to isolate the active principles of natural extracts, resulting in the use of many of these agents in medicine. Synthetic methods have been developed since the mid‐nineteenth century permitting the synthesis of clinically useful semisynthetic analogues of pharmacologically active natural products. Synthetic methods have resulted in the generation of purely synthetic structures that are not found in the natural world and have been investigated as potential therapeutic agents. The development of automated parallel and combinatorial syntheses has vastly increased the number of compounds that can be synthesised in any given period of time. Drug design strategies have been developed since the mid‐twentieth century allowing a more focussed approach to the discovery of novel agents. In the last couple of decades, genomics and proteomics have identified huge numbers of novel targets for future drug research. Structure‐based drug design involving X‐ray crystallography and molecular modelling has been developed over the last 30 years allowing researchers to investigate how active compounds interact with their targets at the molecular level, and allowing the rational design of new and improved analogues. De‐novo drug design has been developed over a similar period allowing scientists to study a binding site, then design novel structures in silico as potential lead compounds. In the past 20 years, fragment‐based drug design has been used to discover novel ligands for protein targets.