Drugs, DNA, and Proteins: Life in Three Dimensions

Life exists in a tri-dimensional space. This is the reason for one of my pet peeves about some textbooks — which may be great otherwise. When talking about cells, molecules, etc., their tridimensional character is not explicitly stated or even alluded to.

Failing to address this fact is exactly like drawing a stick figure on a whiteboard and referring to it as a proper human.

A consequence of this practice in some science books is that they show cells in an overtly simplified fashion.

In all fairness, this is necessary for the sake of simplicity and clarity, but then again, in reality, cells are molecularly crowded, as illustrated below.

The drawing above represents a mycoplasma cell, one of the simplest, mind you…

As evidenced above, there is an intrinsic complexity in each and every cell that we must take into consideration when discussing molecular interactions, including the interactions between drugs and bodily systems. This is particularly important because all living beings are made of at least one cell and oftentimes many. Therefore, as far as drugs are concerned, there are multiple potential targets in any given organism that can affect the physiological response to a particular molecule. This wide variety of potential targets are usually proteins, which are the result of gene expression, which in turn will bring us, albeit briefly, to DNA.

What Does DNA Do?

Virtually everybody nowadays is familiar with the letters “DNA” (deoxyribonucleic acid), even if what immediately comes to mind are police TV shows. In fact, there are many, and I mean many, popular and technical science books that masterfully explain the basics of DNA biology. Therefore, I will refer you to a couple of them if you want to know more about DNA itself, these are available in the Resources in the sidebar to the right of this article.

Most people have a notion that DNA is somehow responsible for what we look like, how does our bodies work, and how we behave (to a certain extent at least). Well, DNA does none of these things… at least directly.

Surprised? The truth is that DNA is essentially an information storage molecule; by itself, it hardly does anything.

For DNA to “work,” the information it contains needs to be decoded and converted into a useful form, namely proteins, which are the entities capable of actually doing the things that life does.

In other words, proteins are the “muscle” behind DNA’s “brains.”

Proteins and Biological Processes

Proteins are the major type of molecule in charge of pretty much all the multiple biological processes that drug development is concerned with.

For example, some proteins determine the size and shape of cells, and others deal with how to generate the chemical energy necessary for cells to function. Other proteins serve as gatekeepers between the cell and the environment and yet other proteins of multiple kinds are responsible for the myriad of chemical reactions that run the cell’s business. Since each and every one of those proteins modulates normal physiological events, they all are potential targets for drugs.

The main point is that for any drug-protein interactions to occur there must be some physical contact between the drug and its protein target. In general terms, we can refer to a protein targets as receptors, which may include several types of molecules such as ion channels, enzymes, transporters, and similar molecules. Scientists refer to all these targets collectively as receptors.

The Receptor Concept

The receptor concept is one of the cornerstones of pharmacology. Once we humans understood that the effect of potions, herbs or bee stings was not due to magic but rather to chemical phenomena, it was self-evident that the chemistry of the potion somehow intermingled with the chemistry of the body to elicit any observable effects. I especially like the way two scientists expressed this in a 1977 paper by Ariëns and Beld:

“A proper understanding of drug action requires a molecular approach, since a bioactive agent can only induce a pharmacological effect in a biological object as the result of an interaction between its molecules and certain counterparts in the biological object.”

And alternatively, as one of the fathers of pharmacology, Paul Ehlrich said:

“Corpora non agunt nisi fixata.”(Entities cannot interact unless in contact with each other; see Klotz, in the”resources” section).

Therefore, there must be a physical contact between a toxin and its receptor – and by extension, any and all toxin-receptor interactions depend on the 3D character of both the toxin and the specific region of the receptor that it interacts with for such contact to occur.

Receptor theory had two main pioneers.

• John Langley (1852-1925), proposed in 1905 that chemical compounds induce their effects by interacting with “receptive substances”, which today we know them simply as “receptors”.
• Later on, Paul Ehlrich (1854-1915, who we saw above) formally proposed that “…there must be a specific chemical character of the cell that is responsible for the selective binding of dyes”. Ehlrich named these still hypothetical entities “side chains” and later on, coined the term that we still use today, “receptors”. He seemed to have a knack for nomenclature; he also coined the term “chemotherapy”, also still in use today. Ehlrich also proposed that it was possible to find or create medications that act as “magic bullets” against diseases like cancer.

In a real sense, all of pharmacology evolved as a continued search for magic bullets, a search still ongoing in full force today.

Ligands: The Right Key for the Right Lock

On the other side, a chemical entity that associates to a receptor’s binding site is technically called a ligand. This ligand-binding site connection can be likened to the relationship between a key and a lock. Only a ligand that has the right size and shape will be able to bind to the receptor target, the ligand being the key and the receptor site being the lock.

More terms: An agonist would open the hypothetical door; an antagonist can get into a lock, but it is the wrong key, so it will not open the door and if stuck (and that’s the key to understand agonists/antagonists; pun absolutely intended), the antagonist will prevent the right key from going in and therefore will inhibit the physiological process.

Drug and Target Relationships Are Complex

The relationship between a drug and its target seems straightforward, but in most cases is anything but. Both the specific structural features of both the ligand and its receptor are crucial to achieve the proper physiological effect; this is directly related to the tridimensional nature of cells and molecules alike, that we mentioned at the beginning of this post.

Chemists, professional and amateur alike, are taking advantage of these properties to design molecular entities capable of alleviating disease or to induce psychoactive states. These are interesting (and terrifying) times.

© Copyright 2015 Oné Pagán, PhD, All rights Reserved. Written For: Decoded Science