Historical Background to Drug Discovery

labTherapeutic drugs have played a major role in increasing average life expectancy in the United States in the last century.

However, while many of the drugs in use in the last fifty years or more have been of synthetic or semi-synthetic origin, the pharmacopoeias prior to that period were of natural origin.

The medicinal value of plants has been recognized by almost every society on this planet. In the nineteenth and earlier centuries, natural product extracts, particularly those derived from botanical species, provided the main source of folk medicines. lab In the latter part of the nineteenth century, biologically-active organic molecules began to be isolated in relatively pure form for medicinal use. For example, salicyclic acid, the precursor of aspirin, was isolated in 1874 from willow bark. More potent painkillers, such as morphine and codeine, were isolated from the opium poppy. The anti-malarial agent quinine was separated from cinchona (china bark). The leaves of the purple foxglove plant provided an excellent source of digitalis that was purified for use against heart disease. There are numerous other examples. Although synthesis of the first synthetic pharmaceutical drug, aspirin, occurred in the latter half of the nineteenth century, it was not until the early 1900s that the recognition of aspirin as a universal pain reliever was realized and this discovery spawned the era of therapeutic agents.


It was not until the recognition that many infectious diseases were caused by microorganisms that the real impetus in the development of therapeutic agents, both natural and non-natural, began to occur. Concurrent with the discoveries in medical microbiology were major advances in synthetic organic chemistry and biochemistry that provided further momentum in the area of therapeutic agents. Synthetic sulfa drugs, the natural antibiotic penicillin, from Penicillium notatum (Alexander Fleming), the semi-synthetic antibiotic tetracycline, produced from natural chlortetracycline elaborated by Streptomyces aureofaciens (Benjamin Duggar) and the anti-tubercular aminoglycoside streptomycin, from Streptomyces griseus (Salman Waksman), were all landmark discoveries of the 1930s and 1940s. The importance of vitamins and diseases caused by their deficiencies were also being uncovered during this period. During the next several decades advances in X-ray crystallography, NMR spectroscopy and mass spectrometry, and developments in electrophoresis, ultracentrifugation, HPLC and other technologies contributed to the discovery of additional chemical entities with therapeutic activities and to the development of some vaccines. Selected examples include oral contraceptives (Margaret Sanger, Katherine McCormick, Russell Marker, Gregory Pinckus and Carl Djerassi), tranquilizers (e.g., valium) and poliomyelitis vaccines (Salk and Sabine).


The seeds for the concept of rational drug design were laid in the 1940s and 1950s by George Hitchings and Gertrude Elion in their work on DNA-based antimetabolites, which led to the discovery of modified purines with anticancer activity. However, the era of DNA and medicine was largely stimulated by the elucidation of the double-helical structure of DNA by Watson and Crick in 1953. The ramifications of this discovery in DNA replication, transcription and translation led to a much better understanding of viral replication. This laid the foundation for antiviral drug discovery in subsequent decades as molecular targets in the viral replication cycle began to be identified. The 1950s also saw the discovery of vancomycin, a glycopeptide which was developed much later for use against methicillin-resistant staphylococci infections. The era of recombinant DNA technology and molecular cloning began around the mid-1970s. Spectacular accomplishments in the area of synthesis of complex, biologically-active natural products also occurred during this period including the monumental synthesis of vitamin B12 by Nobel Prizewinner, R. B. Woodward, and his research team, which included Vasu Nair. The natural product, taxol, isolated from Taxus brevifolia in 1971, represents an excellent example of the combination of natural product isolation and organic synthesis in the development of an anticancer agent. Taxol finally progressed into clinical use in 1993. Developments in molecular biology and virology had a major impact in the scientific understanding in the 1980s and early 1990s of the replication of the retrovirus, HIV. Identification of the possible biochemical points of attack on the virus replication cycle gave drug discovery efforts around the world major impetus for the design and synthesis of nucleoside, non-nucleoside and peptide analogs as targeted anti-HIV agents. The emergence of a drug-resistant virus of both natural and non-natural origin has complicated the therapeutic picture considerably and has necessitated the use of drug combination therapy. The polymerase chain reaction (PCR) of the 1980s resulted in major advances in biotechnology that have had significant impact in drug discovery. In the 1990s, combinatorial chemistry, high-throughput screening, molecular modeling and bioinformatics contributed to the discovery of newer generation drugs based on genomics and proteomics.


The first few decades of the 21st century will see further advances in drug discovery that will likely be based, among other areas, on state-of-the art chemistry and chemical biology, enzyme-based molecular syntheses, advances in cellular biology and microbiology, advanced understanding of cell signaling pathways and their consequences, recombinant biomolecules, advanced high-throughput screening, proteomics and genomics, gene and cell therapy, stem cell research, translational sciences and personalized medicine.

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