Combinatorial Libraries

 

Combinatorial refers to multiple configurations of similar compounds.

Combinatorial technology offers specific therapies for individuals when it is used in drug design and development.

One day it will provide a platform to develop personalized cures with less side effects.

Researchers, armed with robotic software and bio-synthesizers, now compile DNA snippets and use them to search for unique receptor markings. This information can then be used to search for cures and prevent malfunctioning. 

Combinatorial chemistry is a digital representation of all chemical possibilities.

Within the protein library there are twenty amino acids and in genetic material there are only four de-oxyribonucleic acids that makes up DNA. 

Thus there is a finite number of molecules that can be formed from these building blocks, especially if we limit the chain length in proteins to say, 5 amino acids and the 15 nucleic bases that potentially code for them. This library could then be subjected to bindings by ligands.

The proteins and DNA that are formed from these combinations were previously thought to have infinite possibilities. And they may. But by limiting the active zone or binding domain to five amino acids or 20 nucleic acids, a library can be synthesized that contains all volumes possible.

Nature often uses five amino acids in constructing her binding domains or active sites.

Antibodies and cell membrane receptors are alike in that they are both composed of amino acids. In some cases the protein is very large (antibody), in others it is not. Binding is immaterial to the size of the protein. Binding is limited to a selected area of a few amino acids. Once bound, a cascade of reactions follow.

While the size of antibodies and cell receptors varies, they both depend on a small segment, typically five amino acids long. This five amino acid are is the active site and is involved in binding and recognition.

The number of possible combinations of five amino acids approximates five million, but the actual number of combinations actually created by Nature is far less.

By varying one or two amino acids within the sequence, Nature varies the binding domain and thereby varies the ligands that will bind with it.

Ligands are entities that chemically bind to a receptor.  

Antigen binding to antibody is the classic example of the ligand binding to a receptor.

This is the language of nature. It is an interactive mechanism based on receptor chemistry. Receptor binding is the glue that keeps the sciences together.

It is the 0 and 1s of biology, the up and down, yin yang of the universe. Bindings are the language of Nature.

One of the innovations provided by combinatorial chemistry is the potential to recognize patterns in nature by testing these bindings.

 

The limited diversity in humans is attributed to the closeness of our DNA and the finite number of nucleotide possibilities it provides.

There appears to be a trend towards auto-immune diseases in people without any history of allergies or other immune based reactions. This may be due to the inordinate number of pesticides, colorants and preservatives our food has been processed with.

Many digestive disorders originate from an immune response to something it shouldn't have. Immune responses involves large antibodies that recognize and position themselves relative to the marker it will mate with.

 

The antibody binding sites involves only a small number of amino acids. This limits their diversity. It also enables faster drug discovery.

There are a finite number of binding domains embedded in antibody receptors. What used to be hot or miss, trial and error is now meticulously clean.

The binding of antigen to an antibody initiates the recognition and removal of the ligand from the body.  

This is an immunological response.

The ligand-receptor complex initiates a wave of inflammation. How the complex is recognized and handled by the body affects health.

Health depends on the binding of cell receptor with its proper ligand. Disease results in the improper binding of receptors.

 

Combinatorial Drug Design

The molecular lock and key method to drug discovery involves the painfully slow process of trial and error to determine the right fit that can bind with the target receptors and block the cascade.

Mechanisms can be blocked by drugs that occupy a cell’s membrane receptors. These receptors are the currency of biological communications.  The binding of insulin, the five senses, hormones, growth, blood pressure, thinking  are all the result, on a molecular level, of an interaction between a ligand and a receptor.

Combinatorial Chemistry is a paradigm shift in drug discovery. It was invented in order to follow a more predictable route to ligand discovery. Put simply, a library is a collection of all possible combinations of similar molecular compounds.

Combinatorial chemistry is based on a finite universe of molecular possibilities. Combinatorial chemistry, as originally conceived by its inventor, Dr. George Pieczenik, utilized a virus library containing small peptide chains and sequences of nucleic acids.

Each viron particle containing one sequence for example of, five amino acids. These are the “locks” and are located on the outer envelope of the virus particle with the corresponding DNA (code) inside.

According to combinatorial theory, each unique conformation of chemically identical molecules can interact in opposing ways or on opposing receptors to effect change. It is precisely for this reason that The Athlete’s Diet recommends whole plants. Whole plants produce different and more balanced results than those caused by the extracted solitary compound.

Whole plants are better  because of the inclusion of all the plant’s compounds, not only the one identified by researchers. Furthermore, modifying one of nature’s compounds in order to obtain a patent and thereby profit from it, as is the case with pharmaceutical drugs, removes some of the built in balances of the plant. Could this be an explanation for the toxic side effects or addictive properties that pharmaceutical drugs are known to have? Could this be the reason that the poppy flower and the coca leaf are less addictive than their refined and processed children (cocaine and heroin)?

Although the Athlete’s Diet advocates supplementing the diet with colorful antioxidants, nothing can replaces the balance of the original whole plant.

Botanical drugs are safe than pharmaceutical ones because they contain a series of compounds instead of just one.  As a series of molecules, they switch on different receptors based on the conditions at the time.  At another time or in another person, a different set of switches might be triggered.

This is the opposite to pharmaceutical drugs that achieve their result by overwhelming activity at one type of receptor.

Botanical Libraries

The uniqueness of each plant includes the color it displays and its medicinal properties. These characteristics can all be traced to the phytochemical compounds found in the plant’s cells.

The library of any specific plant contains multiple forms of similarly structured compounds. They are chemical cousins. Nature created this library of compounds via the DNA of the plant and locked them in the stems, roots, and leaves of plants.

The library of compounds are released when the plant is  heated or its fibers eaten and exposed to the body’s digestive juices.  Its molecules when free to be transported via the blood direct themselves to the sites of injury, inflammation and free radical generation. These compounds help humans survive.

Plants are provided with a universe of similarly structured chemical compounds so the plant can adapt to a changing  environment. The effect any one of these compounds produce in humans is unrelated to its role in the plant’s health.

Plant activity is dependent on receptor binding, the same mechanism of hormones, neurotransmitters and drugs.

The cumulative effects of plants are almost always beneficial because nature’s creations are have a built in balance that drugs lack.  Plants rarely produce harmful side effects because they contain multiple isoforms. Plants act in opposing manners precisely because their botanical compounds are found in multiple versions with differing spatial orientations.

The importance of multiple isoforms is that each form can bind with a different receptor. Sometimes an effect occurs only because a second or possibly third receptor is activated. This moderates their effects and makes them less harmful than manufactured drugs.

Nature created libraries of compounds, not solitary ones. Nature’s library provides the plant with a large volume of compounds. Some are active and others are supportive. Many have no known purpose but all are probably necessary.

The interaction that occurs within any cell is a result of a specific phytochemical binding with a specific receptor on a cell membrane. This has the effect of creating an on or off switch or rather a series of switches.

Depending on the phytocompound and the receptor involved, activity is directed by the receptor-ligand binding.  It is through this interaction that changes within the cell occurs. The fact that variations in phytocompounds and receptors exist indicates that this variation in nature has a purpose.

Molecular reactions between receptors and ligands drive life’s processes. Whether it is between a hormones and a cell, or an enzyme and substrate a chemical bond between a ligand and a receptor takes place. Other examples include synapse and neurotransmitter, the movement of sodium and potassium across a neuronal membrane or vision and light, hearing and sound and touch and feel.

Nature’s Combinatorial Libraries describes the existence of a few, almost identical compounds in a plant. The purpose of slight variations or similar combinations of atoms may be related to the on and off switches of biological systems.  Different sets of biological receptors counteract each other to produce opposing effects.

A plant’s value to humans is due to its multitude of compounds or natural library. The library is a combinatorial series of compounds that chemically differ slightly. Since they either bind or do not bind, their opposing effects could not be greater.

The result of proper bindings is normal growth and repair.. Faulty binding leads to malfunction and disease.