Learn Dynamics Of ‘Target-Ligand’ Interactions To Understand ‘Similia Similibus Curentur’
To understand the scientific interpretation of ‘similia similibus curentur’ in its real perspective, one should know the fundamentals of ‘target-ligand’ relationships and dynamics of ‘bio-molecular inhibitions’.
There are diverse types of molecular ‘targets’ such as receptors, enzymes and antibodies which interact with appropriate ‘ligands’, so that the biochemical pathways underlying vital processes are maintained unhindered. Knowledge of the real molecular dynamics involved in ‘ligand-target’, ‘signals-receptors’, ‘substrates-enzymes’ and ‘antigen-antibody’ interactions is essential for understanding the science behind ‘similia similibus curentur’.
A receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism. These signals tell a cell to do something—for example to divide or die, or to allow certain molecules to enter or exit the cell.
In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach. A molecule which binds (attaches) to a receptor is called a ligand or ‘signal’, and may be a peptide (short protein) or other small molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin. Each kind of receptor can bind only certain ligand shapes. Each cell typically has many receptors, of many different kinds. Simply put, a receptor functions as a keyhole that opens a neural path when the proper ligand is inserted.
A ligand may be a whole molecule, a functional group, a moiety or even a radical or free ion.
Ligand binding stabilizes a certain target conformation (the three-dimensional shape of the target protein, with no change in sequence). This is often associated with gain of or loss of protein activity, ordinarily leading to some sort of cellular response. However, some ligands (e.g. antagonists) merely block target molecules, without inducing any response. Ligand-induced changes in targets result in cellular changes which constitute the biological activity of the ligands. Many functions of the human body are regulated by these diverse types of biological target molecules responding uniquely to specific ligand molecules like this.
Studies on the the shapes and actions of target molecules, especially receptors and enzymes have advanced the understanding of drug action at the binding sites of biological molecules.
Depending on their functions and ligands or signalling molecules, several types of receptors may be identified:
Some receptor proteins are peripheral membrane proteins.
Many hormone and neurotransmitter receptors are transmembrane proteins: transmembrane receptors are embedded in the phospholipid bilayer of cell membranes, that allow the activation of signal transduction pathways in response to the activation by the binding molecule, or ligand.
Metabotropic receptors are coupled to G proteins and affect the cell indirectly through enzymes which control ion channels.
Ionotropic receptors (also known as ligand-gated ion channels) contain a central pore which opens in response to the binding of signalling molecule.
Another major class of receptors are intracellular proteins such as those for steroid and intracrine peptide hormone receptors. These receptors often can enter the cell nucleus and modulate gene expression in response to the activation by the ligand.
One measure of how well a molecule fits a receptor is the binding affinity, which is inversely related to the dissociation constant. A good fit corresponds with high affinity and low dissociation constant. The final biological response (e.g. second messenger cascade, muscle contraction), is only achieved after a significant number of receptors are activated.
The receptor-ligand affinity is greater than enzyme-substrate affinity. Whilst both interactions are specific and reversible, there is no chemical modification of the ligand as seen with the substrate upon binding to its enzyme.
Many pathological molecular errors are caused by inhibitions of these target molecules such as receptors and enzymes by binding of exogenous or endogenous molecules or ions on them. Bacterial toxins, drugs and such pathological agents act this way.
Dynamcs of ‘ligand-target’ interactions can be understood only if we have a working knowledge of protein chemistry, especially enzyme chemistry.
There exist millions of protein molecules belonging to thousands of protein types in a living organism. Each protein molecule is formed by the polymerization of monomers called amino acids, in different proportions and sequences. Each protein type has its own specific role in the bio-chemic interactions in an organism. Most of the amino acids necessary for the synthesis of proteins are themselves synthesized from their molecular precursers inside the body. A few types of amino acids cannot be synthesized inside the body, and have to be made available through food. These are called essential aminoacids. There are specific protein molecules assigned for each bio-chemic process that take place in the body. Various proteins play different types of roles, like biological catalysts or enzymes, molecular receptors, transport molecules, hormones and antibodies. Some proteins function as specialized molecular switches, systematically switching on and off of specific bio-chemic pathways. Proteins are synthesized from amino acids, in conformity with the neucleotide sequences of concerned genes, with the help of enzymes, which are themselves proteins. ‘Protein synthesis’ and ‘genetic expression’ are very important part of vital process. It may be said that genes are molecular moulds for synthesizing proteins. There are specific genes, bearing appropriate molecular codes of information necessary for synthesizing each type of protein molecule. Even the synthesis of these genes happens with the help of various enzymes, which are protein molecules. There is no any single bio-molecular process in the living organism, which does not require an active participation of a protein molecule of any kind.
The most important factor we have to understand while discussing proteins is the role of their three-dimensional spacial organization evolving from peculiar di-sulphide bonds and hydrogen bonds. Water plays a vital role in maintaining the three dimensional organization of proteins intact, thereby keeping them efficient to participate in the diverse biochemical processes. Proteins exhibits different levels of molecular organization- primary, secondary, tertiary and quaternary. It is this peculiar three dimensional structure that decides the specific bio-chemical role of a given protein molecule. More over, co-enzymes and co-factors such as metal ions and vitamins play an important role in keeping up this three-dimensional structure of protein molecules intact, thereby activating them for their specific functions.
Whenever any kind of error occurs in the particular three-dimensional structure of a given protein molecule, it obviously fails to interact with other bio-molecules to accomplish the specific functions it is intended to play in the concerned bio-chemical processes. Such a failure leads to harmful deviations in several bio-chemical processes in the organism that require the participation of this particular protein, ultimately resulting in a cascading of multitude of molecular errors. This is the fundamental molecular mechanism of pathology, which we perceive as disease of some or other category. These deviations in bio-chemical pathways are expressed as various groups of subjective and objective symptoms of disease. The organic system exhibits a certain degree of ability and flexibility to overcome or self repair such molecular deviations and preserve the state of homeostasis required to maintain life. Anyhow, if these deviations happen in any of the vitally decisive bio-chemical pathways, or, if these are beyond self repair, the bio-chemical processes ultimately stop and death happens.
Almost all conditions of pathology we normally confront, including those resulting from genetic origin, are involved with some or other errors or absence of some protein molecules that are essential for concerned bio-chemical processes. Moreover, most of such molecular errors other than genetic origin, arise due to binding of some exogenous or endogenous foreign molecules or ions on the active, binding or allosteric sites of protein molecules, effecting changes in the three-dimensional configurations of protein molecules. A host of diseases originating from viral-bacterial infections, allergies, miasms, poisoning, drugs, food etc, belong to this category.
The most important factor we have to bear in mind when talking about kinetics of proteins in general and enzymes in particular is their highly defined, peculiar specificity. Each type of protein molecules, or some times even some part of a single protein molecule, is designed in such a way that it can bind only with a specific class of molecules, and hence participate in a specific type of bio-chemical interaction only. This functional specificity is ensured through the peculiar three-dimensional configuration of the protein molecules, exhibited through their characteristic folding and spacial arrangement. Reactive chemical groups known as active sites, binding sites, and regulatory sites are distributed at specific locations on this three dimensional formations of protein molecules. These chemical groups can interact only with molecules and ions having appropriate configurations that fit to their shape. This phenomenon can be compared with the relationship existing between a lock and its appropriate key. Just as a key with an exactly fitting three dimensional shape alone can enter the key hole of a lock and open it, molecules with exactly fitting three dimensional structures alone can establish contact and indulge in chemical activities with specific protein molecules. This key-lock relationship with substrates defines all biochemical interactions involving proteins, ensuring their optimum specificity. Obviously, any deviation in the three dimensional configuration of either lock or key makes their interaction impossible.
It has been already explained that the primary basis of any state of pathology is some deviations occurring in the biochemical processes at the molecular level. Endogenous or exogenous foreign molecules or ions having any functional moieties with configurational similarity to certain biochemical substrates can mimic as original substrates to attach themselves on the regulatory or the active sites of proteins, effecting changes in their native 3-D configuration, thereby making them unable to discharge their specific biochemical role. This situation is called a molecular inhibition, which leads to pathological molecular errors. It is comparable with the ability of objects having some similarity in shape with that of key, to enter the key hole of a lock and obstructing its function. As a result of this inhibition, the real substrates are prevented from interacting with the appropriate protein molecules, leading to a break in the normal biochemical channels. These types of molecular errors are called competitive inhibitions. It is in this way that many types of drugs, pesticides and poisons interfere in the biochemical processes, creating pathological situations. Such substances are known as anti-melabolities.
When we prove our drugs in healthy people, the constituent molecules contained in the drug substances may bind to diverse types of ‘receptors’ and enzymes’ due to the similarity of configurations between functional groups of original ligands and drug molecules. Molecules having functional moieties with ‘similar’ configuration can bind to similar target molecules, causing similar pathological molecular errors expressed through ‘similar’ subjective and objective symptoms. The concept of ‘similarity of symptoms’ can be scientifically understood if we know the dynamics of ‘ligand-receptor’ and ‘substrate-enzyme’ relationships. Without this fundamental understanding one cannot follow my concepts regarding ‘potentization’ and ‘similia similibus curentur’.