History of Drug Discovery

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.

Keywords: drugs; history of drugs; drug discovery; drug design; drug development; medicinal chemistry

Figure 1.

Alkaloids with pharmacological activity. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 2.

Cinically important alkaloids discovered in the nineteenth century. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 3.

Clinically important nonalkaloids discovered in the nineteenth century. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 4.

Semisynthetic analogues of alkaloids. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 5.

Synthetic analogues. Reproduced with permission from Sneader .

Figure 6.

Analogues of phenazone. Reproduced with permission from Sneader .

Figure 7.

Cocaine and procaine. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 8.

Synthetic drugs. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 9.

Examples of important drugs obtained from the natural world in the latter half of the twentieth century. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 10.

Examples of hormones. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 11.

Adrenaline and analogues. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 12.

Development of beta‐blockers. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 13.

Development of statins. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 14.

Oestrogenic compounds. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 15.

The development of oral progesterones. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 16.

Development of steroidal anti‐inflammatory agents. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 17.

Development of antihistamines. Reproduced with permission from Sneader .

Figure 18.

Promethazine and chlorpromazine. Reproduced with permission from Sneader .

Figure 19.

Monoamine oxidase inhibitors used as antidepressants. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 20.

Tricyclic antidepressants. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 21.

Selective reuptake inhibitors. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 22.

Histamine antagonists used in antiulcer therapy. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 23.

Development of the proton‐pump inhibitors. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 24.

Antibacterial agents used in ulcer therapies. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 25.

Examples of clinically important opioid analgesics. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 26.

Trypan red. Reproduced with permission from Sneader .

Figure 27.

Organoarsenic agents. Reproduced with permission From Sneader .

Figure 28.

Suramin. Reproduced with permission from Sneader .

Figure 29.

Prontosil rubrum (sulfamidochrysoidine). Reproduced with permission from Sneader .

Figure 30.

Beta‐lactam antibacterial agents. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 31.

Alkylating agents. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 32.

Folic acid. Reproduced with permission from Sneader .

Figure 33.

Antimetabolites used in the treatment of cancer. Reproduced with permission from Sneader .

Figure 34.

Protein kinase inhibitors used in the treatment of cancers. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 35.

Antimetabolites used in antiviral therapy. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 36.

Saquinavir. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 38.

Protease inhibitors used in the treatment of hepatitis C. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 39.

Antiflu drugs. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 41.

The use of Allegrow software to ‘grow’ a ligand in a binding site. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 42.

Fragment‐based drug design. Reproduced from Patrick with permission of Oxford University Press (www.oup.com). © Oxford University Press.

Figure 37.

HIV‐1 protease enzyme with bound saquinavir (from pdb file 1HXB).

Figure 40.

Left: Partial ribbon structure of a protein kinase containing the anticancer drug imatinib represented by grey spheres. Right: Detailed image of the binding site showing imatinib (spheres) interacting with amino acid residues (sticks). Image created from pdb file 1IEP, obtained from the RCSB Protein Data Bank.

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Further Reading

Mann J (1996) Murder, Magic, and Medicine. Oxford: Oxford University Press.

Stockwell BR (2011) The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines. New York, USA: Columbia University Press.

Weatherall M (1990) In Search of a Cure: A History of the Pharmaceutical Industry. Oxford: Oxford University Press.

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Patrick, Graham L(Jun 2013) History of Drug Discovery. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003090.pub2]