Chapter 11: Designing Drugs and Manipulating Molecules

Chemistry touches many aspects of everyday life. It is interesting that the majority of the class listed the chapter on drugs as their highest priority for discussion. Clearly in the approximate two lecture periods we have left we cannot tell you everything you ever wanted to know, but perhaps we can help you make a connection between the fundamental ideas underlying drug action and the chemistry involved in those ideas.

What is a drug? We might define it as a single chemical substance that is an active ingredient in a medicine. Therefore, there is a subtle difference between the term medicine and drug. Some medicines may, in fact, contain several drugs as components. If you search the pharmacy shelves for treatments for cold symptoms, for example, you will find some of the medicines available consisting of several different drugs, each presumed to treat a different aspect of cold symptoms.

In everyday use by the public, the term "drug" had pretty negative connotations. We have reports of "drug dealers", people doing things under the influence of drugs, and athletes screened for the use of "performance enhancing" drugs. We are all used to the slogan aimed at young people—"Just say no" to drugs.

Yet drugs, in the form of medicines, have greatly enhanced our quality of life over the last century. We have treatments for many diseases that would earlier have been very debilitating or have led to an early death. We can correct through medication a number of abnormalities in normal functioning of the human body. We have made possible life-saving operations such as heart transplants. So drugs are like the proverbial two-edged sword. There is a good side and a bad side, and only by understanding them and what they do can we hope to harness the good and avoid the bad.

The pharmaceutical industry is a greater than $billion dollar industry that is in the business not only of manufacturing drugs for our use, but in discovering new drugs to treat conditions that have no current treatment, or to improve the efficacy of existing drugs. Some drugs are expensive because the process of developing them is expensive.

Let me cite a local example. For many years the search for a cure for cancer has taken many guises. One of them was the search for new chemical compounds that would preferentially inhibit the growth of cancer cells. Among thousands, maybe millions, of compounds tested by the National Cancer Institute, one was particularly promising. It was obtained from the bark of the Pacific Yew tree, and has been called by several names, perhaps the most recognizable, taxol. From the following chemical structure, you can see that taxol is a very complicated organic molecule:

(Click on the image above to see the structure in 3 dimensions, using the Chime plugin).  At first, taxol was a potential drug that no drug company was particularly interested in, especially since the discovery had been through some government supported screening. The National Institutes of Health, which is responsible for funding much of medical research today, had to offer some special incentives for a drug company to take on the job of further testing and producing taxol as a viable anti-cancer drug. Bristol-Myers Squibb obtained the right for exclusive development and sales for a period of some years in return for their investment in the development stages of the drug.

One problem with the drug was the need to cut down Yew trees in order to obtain the bark for extraction. Environmentalists became extremely concerned, since the need for the bark could conceivably lead to destruction of all available Pacific Yew trees.

The needles of the Yew tree make a compound similar to taxol, a compound that can be converted to taxol in a few chemical steps. Professor Robert Holton developed a chemical procedure for this conversion, obtained patent rights to the procedure, and has licensed the procedure to Bristol-Myers Squibb as a means of "semisynthetic" production. Through his licensing, Florida State University has now earned close to 100 million dollars in fees, 4.5% of the gross income from sales of the drug.

This illustration highlights two conclusions:

The potential market worth of drugs.

The importance of understanding chemistry in drug production.

How do drugs get discovered? Where do they come from? How do they work? These questions are not simply answered. In fact, after a year’s course in pharmacology, you still wouldn’t be experts in all the details involving drug discovery and production and mechanism of drug action.

Let’s first look at the variety of things which drugs are used for. One classification of drugs could be done according to the application.

Antibiotics, anti-viral, anti-parasitic

These are drugs meant to kill disease-causing organisms. They often take advantage of the fact that there may be a slight difference in some metabolic enzyme or activity of the organism compared to that of the infected cell. Penicillin, for example, blocks the synthesis of a cell wall of bacteria. Animal cells have no cell walls of this type, so they are not affected by penicillin. Often the treatment of such diseases is through a process called vaccination, in which the body’s immune system is activated to help in destroying the invading organism. The vaccine contains a molecule similar in structure to some part of the invading organism which triggers an immune response whenever the cells or our immune system encounter such a molecule.

 

Such drugs can often be curative.

Anti-cancer

Cancer cells are cells that have lost the natural control over growth and proliferate to the detriment of the whole organism. They are somewhat like an infectious agent, but they arise from normal cells. Some cancers are, in fact, caused by infectious viruses which change or mutate something in the regulatory pathway for cell growth and division. Treatment of cancers by drugs is called chemotherapy. Because the cancer cells are generally derived from normal cells, it is much more difficult to find some agent that will destroy the cancer cells without destroying normal cells in the individual.

 

Such drugs can in some cases be curative, but they generally work only to slow growth of cancer cells and they depend on the natural immune system to wipe out the last traces of the cancer.

Cardiovascular drugs

These would include drugs that affect many different aspects of the circulatory system and the cells involved in that system. Among them would be drugs to treat abnormal or dangerous conditions such as high blood pressure, elevated serum cholesterol, impaired blood flow to the heart and weakened heart muscles, and malfunctioning of the kidneys.

Psychoactive Drugs

analgesics       block pain

sedatives        induce sleep

stimulants       increase energy and physical activity

tranquilizers   calming effects

narcotic           block nervous system action

hallucinogen  alters mind and perception

 

These drugs are usually used to treat some kind of symptom. Treatment of pain, for example, does not necessarily remove the underlying cause of the pain. Some of the drugs of this class are addictive, and once they are taken they develop a dependance which is very difficult and painful to break. In some cases individuals develop a tolerance to the drug, which means that it takes ever increasing doses to have any effect. And in some cases habituation can occur, which is a psychological dependance on the drug. Most of these drugs attack some part of the central nervous system.

Immunosuppresive

Many drugs take advantage of, or relate to, the body’s natural defense system which continuously monitor for the presence of foreign material in the blood and develop antibodies and other defense systems to destroy invaders. One of the difficulties posed by this system is that tissue transplants from other individuals are seen as "foreign" by the immune system, and rejection of the transplant would be the major result. The development of drugs that interfered in this recognition and rejection process opened the door for a variety of organ transplants, perhaps the most dramatic being that of a heart transplant. Persons having undergone such a transplant will normally have to stay on immunosuppresive medication for the rest of their lives, otherwise their body will reject the tissue as foreign.

Hormonal regulation

Many processes in the body are under tight hormonal control, involving myriads of chemical substances, from small molecules to medium sized proteins such as insulin and glucagon. Drugs have been developed that block the action of certain hormone molecules (antagonist action), as well as those that mimic hormone action (agonist action). In fact, sometimes the hormones themselves are used as drugs, as is the case with insulin in juvenile diabetes. In this case, something (perhaps a viral infection) has destroyed the ability of the pancreas to produce the hormone insulin. Insulin is required for many metabolic activities, among them simply the uptake of glucose into most cells of the body. The condition is treated by injection of insulin at appropriate intervals in the day. (Too much insulin can cause a drop in blood glucose, starving the brain, and leading to a catatonic state and death).

This is by no means a comprehensive summary of drug targets or types. But you can see an underlying principle that the drugs act somehow to affect the chemical reactions occurring in living cells.

Two of the principle targets for drug actions include enzymes and receptors.

Enzymes are large molecules of protein which catalyze chemical reactions in living organisms. Virtually every reaction except proton transfer is enormously accelerated in rate by these specific catalysts, so that the reactions which do occur in the cell depend on what enzymes are there. Enzymes act by having very specific surface binding sites that are complementary to the molecular structure of the compounds which they cause to react (called their substrates). Substrates bind specifically to these surface sites in the process of the reaction. Many drugs act by mimicking the substrate in structure, binding to the specific site on the enzyme, thereby blocking the binding of substrate and inhibiting the reaction.

Receptors are also protein molecules which are imbedded in the membranes of cells. Hormones and other signaling molecules bind to the surface of a receptor, causing a change in the shape of the receptor which is translated to some interaction just inside the cell membrane that activates an enzyme. This process triggers a series of enzymatic reactions inside the cell leading to some change in the metabolism of the cell. Some drugs act by binding to receptors, either producing the effect of the hormone (agonist activity) or blocking the effect of the hormone (antagonist activity).