A tedious process
Drug discovery has come a long way since the early 1950s where the process was relatively simple and straightforward. During that time, there were no advanced computers or comprehensive databases to help medicinal chemists to discover blockbuster compounds, nor did the scientific community have sufficient capability to screen huge amount of compounds in a short period of time. At that time, the medicinal chemist had to synthesise the test compound one by one. Analytical tools were limited to those such as infrared and UV spectroscopy that had inadequate power when compared to today’s modern equipment. The process of synthesis was also significantly slower with an average of one to three compounds per week from a fully staffed chemistry laboratory. Furthermore, such compounds had to be produced in large quantities (grammes) to accommodate the dosing requirement in animal models (1).
The knowledge and experience of the medicinal chemists were vital to ensure the process of compound discovery and development was successful. However, given the limitations of that era, personal luck seemed to have a big role to play as well. It was common for medicinal chemists to work in silos and they were isolated from other professions. Their role was limited to the early phases of compound synthesis and they generally had no further role when the compound was selected for further development. It was not until the 1980s that pharmaceutical companies began to form multi-disciplinary teams to ensure better efficiency when it came to developing a compound, which resulted in better success rates (1).
The widely used NSAID, Piroxicam, was first developed in 1962 by a two-person team: a medicinal chemist and a pharmacologist. The product discovery and development took nearly two decades, and Piroxicam was only marketed in Europe in 1980 (1).
Combinatorial chemistry and high-throughput screening
The situation had improved considerably since, but the core responsibility of a medicinal chemist still remains. The main difference was the availability of better and more powerful tools to carry the tasks of screening and synthesising compounds. Of the multitude of new “toys” made available to scientists today, two are particularly remarkable in transforming the drug discovery landscape: Combinatorial chemistry and high-throughput screening.
Combinatorial chemistry was once called the “industrialization of chemistry” (2). It is the large-scale implementation of traditional chemistry which allows medicinal chemists to increase their productivity by several magnitudes. The concept of combinatorial chemistry is simple: the chemist will begin by taking several “building blocks” that have different molecular structures, and by leveraging on powerful computers, they synthesise a large number of different compounds by systematically linking these "building blocks" covalently with each other (3). This is akin to playing Lego where different building blocks can be used to create a vast array of compounds.
High-throughput screening, or HTS, is another modern drug discovery tool which relies heavily on advanced robotic, sensitive detectors and powerful software to analyse tens of thousands of compounds within a short time. It is used to identify the affinity of many compounds towards a particular target or a range of targets. HTS is often employed with advanced analytical techniques such as NMR (nuclear magnetic resonance) or LC-MS/MS (liquid chromatography tandem mass spectrometry) (4).
The field of medicinal chemistry will continue to evolve and improve, with better and faster techniques becoming available to scientists to aid drug discovery. With the ever increasing costs involved in developing new drugs, substantial advances in the drug discovery process are hoped to provide much-needed solutions to the pharmaceutical community. MIMS
1. Lombardino JG, Lowe JA. A guide to drug discovery: The role of the medicinal chemist in drug discovery — then and now. Nat Rev Drug Discov. 2004 Oct;3(10):853–62.
2. Mario Geysen H, Schoenen F, Wagner D, Wagner R. A guide to drug discovery: Combinatorial compound libraries for drug discovery: an ongoing challenge. Nat Rev Drug Discov. 2003 Mar;2(3):222–30.
3. Pandeya S, Thakkar D. Combinatorial chemistry: A novel method in drug discovery and its application. Indian J Chem. 2005;44B:335–48.
4. Szymański P, Markowicz M, Mikiciuk-Olasik E. Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests. Int J Mol Sci. 2011 Dec 29;13(12):427–52.
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