- Introduction
- History
- Natural Drug Leads
- Combinatorial Approach
- Discoveries
- Conclusion
- References
- Contact Us
History of Drug Discovery
For thousands of years, indigenous cultures have used local plants and animal products to fulfill their medical needs. As early as the 5th century BC, the Greek physician Hippocrates wrote about the ability of a powder extracted from the bark of willow trees to alleviate aches and reduce the symptoms of fever. However, it was not until the mid-1800’s that the Italian chemist, Raffaele Piria successfully identified and isolated the active ingredient, salicylic acid, from willow bark (Bellis). The second half of the 19th century marked a turning point in medicinal chemistry with a widespread transition from folk medicines to natural product chemistry. The concept of rational drug design really took off in the 1940’s and 50’s inspired in large part by the contributions of George Hitchings and Gertrude Elion (ChemHeritage). Advances in x-ray crystallography, NMR, mass spectrometry, HPLC, and electrophoresis allowed for never before accessible means by which drugs could be developed and tested. By the 1970’s, these techniques had become so advanced that large-scale and time consuming empirical-based screening processes could be avoided.
Around this time, combinatorial chemistry was beginning to take root at the forefront of drug discovery. Chemists such as H. Mario Geysen and Bruce Merrifield developed techniques for solid phase peptide synthesis, spearheading this movement (Geysen). These methods of rapidly synthesizing large numbers of similar peptides allowed for the optimization of compound activity, providing researchers with a practical and efficient means by which they could determine the ideal drug candidates. DuPont chemist, Richard Houghten developed this technique further in what was deemed the, “tea bag,” method (Houghten). In this method, peptides were synthesized attached to plastic bits inside of a mesh bag. He stated that this methods allowed for the acquisition of, "information in a day that you couldn't get in a hundred years before."
High throughput screening was developed between 1989 and 1991 (Lipinsky). This technique employed robotics, advanced software, and sensitive detectors which allowed researcher to quickly preform millions of chemical tests on thousands of compounds. Massive numbers of compounds could now be tested and synthesized in a fraction of the time. Using these and other techniques, Kit Lam produced a library of over one million peptides in 1991. In 1993, Jonathan Ellman created the first library chain of organic heterocycles which are more complex than simple peptides and commonly found in pharmaceuticals. In 1997, the rule of 5 was introduced stating that poor absorption and permeation were inherent in certain peptides based on hydrogen bonding, molecular weight, and other restrictions. This rule has become extremely influential in the world of peptide synthesis, having been cited over 4000 times (Lipinsky).
More recently, PCR and genomics have contributed to the genesis of a new generation of drugs. However, in 2004, drug discovery hit a 24 year low due in large part to a shift away from natural drug sources (Georgia). Currently, programs like Shaman Pharmaceuticals are focusing attention back on natural resources (Bierer). These programs strive to learn as much as they can from indigenous people about local medicinal plants and test them to determine where the benefits lie. The communities are then compensated with programs that they require such as clean drinking water systems and medical care.