A Story of Pharmaceutical Discovery from Long Ago

Many years ago I worked in the herbicide industry. I didn’t want to stay more than a year at ‘the company’ — however my wife, at the time, wanted me to stay longer. [An important object lesson: avoid anything that causes ambivalence when working in the sciences. Work in the sciences can be rewarding, allowing a good, living wage. If you are not happy with the job, find one that makes you happy. At that juncture of my fledgling science career, I wanted to teach chemistry and not be in the lab all day. However, processes of herbicide creation borrowed a lot from the medicinal chemistry creation of the past. It was an education I will never lose.]

However to my benefit,  I learned the steps behind the creation of standard pharmaceuticals (circa 1986). As I labored to advance the corporate philosophy of creating herbicides that could out-perform standard pesticides of the mid-1980s, my mind wandered at times. I learned about a concept called QSAR— it was pioneered in part by scientist named Dr. Corwin Hansch.

The QSAR concept allows the chemist to follow a map of structure activity relationships— it can be qualitative or quantitative. The QSAR model teaches the chemist to modify the molecule via a chemical model of optimizing the drug or herbicide’s effects. Getting to the optimization becomes a road map of sorts.

One of the most important aspects of drug discovery is learning to quantitatively describe a drug’s effectiveness. What I mean by that — one begins with a lead molecule that is effective on a disease or a symptom. The active candidate molecule is modified, using chemical synthesis to produce a more effective molecule or drug. Chemists modify different parts of the molecule until its  effects are   maximized. I will use the aspirin model for the sake of argument.

Aspirin (as we know it) was invented by Felix Hoffman of the Bayer Corporation in present-day Germany in 1899. Getting to aspirin however, stories were passed down of using the bark of the White Willow tree [Salix alba] to alleviate fevers and pain. However, bark of the White Willow tree was effective to a certain point. Bayer chemists isolated multiple compounds from the white willow tree that were eventually named salicylates, (the name is derived from the scientific name for the White Willow tree). So, Bayer chemists wanted to effectively make a better drug. 

The Bayer chemists isolated mixture of salicylates and further reacted them to produce what is known as Aspirin— Acetyl Salicylate. Modifying the lead component or molecule  teaches other chemists what works and what will not work — it becomes a map. In short, to many older chemists, this kind of reasoning is known as a ‘road map problem.’ It is also known as a ‘chicken or egg’ problem. 

The ‘chicken or egg’ problems in science are ubiquitous. A major question that scientists and astrobiologists ponder is how did life begin on Earth? That is a story for another time— it is a rich story that is not fully known, at the present moment. 

References for further discovery:

Alan Wayne Jones,  Early drug discovery and the rise of pharmaceutical chemistry. Drug Testing and Analysis. 2011, 2, 337-344.

Barbora Morra, The chemistry connections challenge: Encouraging students to connect course concepts with real world applications. J. Chem. Educ. 2018, 95, 12, 2212-2215.

Corwin Hansch, et.al.  Chem-Bioinformatics: Comparative QSAR at the Interface Between Chemistry and Biology. Chem. Reviews. 2002, 102, 3, 783-812.