Learn Molecular Kinetics Of Protein Inhibition And Activation, To Understand MIT Explanation Of Homeopathy

MIT is trying to explain homeopathy in terms of removal of pathological molecular inhibitions using molecular imprints of drug molecules contained in potentizef drugs. As such, it is essential that homeopaths should learn the fundemental molecular kinetics of protein inhibition and activation, for understanding the scientific explanations regarding biological mechanism of SIMILIA SIMILIBUS CURENTUR.

A protein inhibitor is a molecule , which binds to proteinsand decreases their activity. Since blocking an essential protein’s activity can produce derangements in the whole down stream molecular processes in that particular biochemical pathway, it leads to a state of pathology. Bacterial and viral toxins, various endogenous or exogenous chemical molecules, drugs and toxic substances can act as protein inhibitors. Protein inhibitors are also used as anti-microbial drugs, herbicides and pesticides .

Not all molecules that bind to proteins are inhibitors; activators also bind to proteons and increase their enzymatic activity. Normal biological ligands of proteins bind to them as part of normal biochemocal interactions and conversions.

The binding of an inhibitor can stop a natural ligand from entering the protein’s active site and/or hinder the protein from performing its normal interactions with ligands.Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with the protein and change it chemically via covalent bond formation. These inhibitors modify key amino acid residues needed for the activity of that particular protein. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the protein, the protein-ligand complex, or both

Many drug molecules are protein inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal protein inhibitor is often judged by its lack of binding to other proteins, and its minimum concentration needed to inhibit the target proteins. A high specificity and minimum concentration ensure that a drug will have few side effects and thus low toxicity.

Protein inhibitors also occur naturally in the body, and are involved in the regulation of metabolism. For example, enzymes in a metabolic pathway can be inhibited by downstream products. This type of negative feedback slows the production line when products begin to build up and is an important way to maintain homeostasis in a living system.

Natural protein inhibitors can also be poisons and are used as defences against predators or as ways of killing prey.

Reversible inhibitors bind to proteins with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to natural ligands and irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the proteins and can be easily removed by dilution or dialysis.

There are four kinds of reversible protein inhibitors.

In competitive inhibition, the natural ligand and the inhibitor cannot bind to the protein at the same time. This usually results from the inhibitor having an affinity for the active site of a protein where the natural ligand also binds; the natural ligand and inhibitor compete for access to the protein’s active site. This type of inhibition can be in certain occasions overcome by sufficiently high concentrations of natural ligand, by out-competing the inhibitor. Competitive inhibitors are often similar in structure to the natural ligand of the protein.

In uncompetitive inhibition , the inhibitor binds only to the protein-ligand complex, it should not be confused with non-competitive inhibitors. This type of inhibition causes a decrease in rate of normal biochemical processes and conversions.

In mixed inhibition , the inhibitor can bind to the protein at the same time as the natural ligand. However, the binding of the inhibitor affects the binding of the natural ligand, and vice versa. This type of inhibition can be reduced, but not overcome by increasing concentration of natural ligand. Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition generally results from an allosteric effect where the inhibitor binds to a different site on a protein. Inhibitor binding to this allosteric site changes the three dimensional conformation of the protein so that the affinity of the natural ligand for the active site is reduced.

Non-competitive inhibition is a form of mixed inhibition where the binding of the inhibitor to the protein reduces its activity but does not affect the binding of natural ligand. As a result, the extent of inhibition depends only on the concentration of the inhibitor.

Natural ligands as well as products also can some time act as protein inhibitors. This happens where either the natural ligand or the product of an enzyme reaction inhibit the same enzyme’s activity. This inhibition may follow the competitive,uncompetitive or mixed patterns. In natural ligand inhibition there is a progressive decrease in activity at high ligand concentrations. This may indicate the existence of two substrate-binding sites in the enzyme. At low substrate, the high-affinity site is occupied and normal kinetics are followed. However, at higher concentrations, the second inhibitory site becomes occupied, inhibiting the enzyme.

Product inhibition is often a regulatory feature in metabolism and can be a form of negative feedback .

Irreversible inhibitors usually covalently modify a protein, and inhibition can therefore not be reversed. Irreversible inhibitor often contain reactive functional groups such as nitrogen mustards , aldehydes , haloalkanes, alkenes, Michael acceptors, phenyl sulfonates , or fluorophosphonates . These electrophilic groups react with amino acid side chains to form covalent adducts. The residues modified are those with side chains containing nucleophiles such as hydroxyl or sulfhydryl groups; these include the amino acids serine, cysteine, threonine or tyrosine. Irreversible inhibitors are generally specific for one class of proteins and do not inactivate all proteins; they do not function by destroying protein structure but by specifically altering the active site of their target.

Proten inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry . Natural poisons are often protein inhibitors that have evolved to defend a plant or animal against predators . These natural toxins include some of the most poisonous compounds known. Artificial inhibitors are often used as drugs, but can also be insecticides such as malathion, herbicides such as glyphosate , or disinfectants uch as triclosan .

The most common uses for protein inhibitors are as drugs to treat disease in modern medicine. Many of these inhibitors target a human enzyme and aim to correct a pathological condition.

An example of a medicinal protein inhibitor is sildenafil (Viagra), a common treatment for male erectile dysfunction. This compound is a potent inhibitor of cGMP specific
phosphodiesterase type 5, the enzyme that degrades the signalling molecule cyclic guanosine monophosphate. This signalling molecule triggers smooth muscle relaxation
and allows blood flow into the corpus cavernosum , which causes an erection. Since the drug decreases the activity of the enzyme that halts the signal, it makes this signal last for a longer period of time.

Another example of the structural similarity of some inhibitors to the natural ligands of the proteins they target is seen in the the anti-cancer drug methotrexate and folic acid. Folic acid is a natural ligand of dihydrofolate reductase , an enzyme involved in making nucleotides that is potently inhibited by methotrexate. Methotrexate blocks the action of dihydrofolate reductase and thereby halts the productionnof nucleotides. This block of nucleotide biosynthesis is more toxic to rapidly growing cells than non-dividing cells, since a rapidly growing cell has to carry out DNA replication , therefore methotrexate is often used in cancer chemotherapy.

Drugs also are used to inhibit enzymes needed for the survival of pathogens. For example, bacteria are surrounded by a thick cell wall made of a net-like polymer called peptidoglycan. Many antibiotics such as penicillin and vancomycin inhibit the enzymes that produce and the cross-link the strands of this polymer together. This causes the cell wall to lose strength and the bacteria to burst.

Drug design is facilitated when an enzyme that is essential to the pathogen’s survival is absent or very different in humans. In the example above, humans do not make peptidoglycan, therefore inhibitors of this process are selectively toxic to bacteria. Selective toxicity is also produced in antibiotics by exploiting differences in the structure of the ribosomes in bacteria, or how they make fatty acids.

Protein inhibitors are also important in metabolic control. Many metabolic pathways in the cell are inhibited by metabolites that control protein activity through allosteric regulation or substrate inhibition. However,nmetabolic pathways are not just regulated through inhibition since proteinbactivation is equally important.

Many herbicides and pesticides are protein inhibitors. Aetylcholinesterase is an enzyme found in animals from insects to humans. It is essential to nerve cell function through its mechanism of breaking down the neurotransmitter acetylcholine into its constituents, acetate and choline. This is somewhat unique among neurotransmitters as most, including serotonin, dopamine , and norepinephrine, are absorbed from the synaptic cleft rather than cleaved. A large number of acetylcholineesterase inhibitors are used in both medicine and agriculture. Reversible competitive inhibitors, such as edrophonium , physostigmine , and neostigmine , are used in the treatment of myasthenia gravis and in anaesthesia. The carbamatenpesticides are also examples of reversible AChE inhibitors. The organophosphate insecticides such as malathion, parathion , and chlorpyrifos irreversibly inhibit acetylcholinesterase. The herbicide glyphosate is an inhibitor of 3-phosphoshikimate 1-carboxyvinyltransferase, other herbicides, such as the sulfonylureas inhibit the enzyme acetolactate synthase. Both these enzymes are needed for plants to make branched-chain amino acids . Many other enzymess are inhibited by herbicides, including enzymes needed for the biosynthesis of lipids and carotenoids andnthe processes of photosynthesis and oxidative phosphorylation. NTo discourage seed predators , pulses contain trypsin inhibitors that interfere with digestion.

Animals and plants have evolved to synthesise a vast array of poisonous products including secondary metabolites , peptides and proteins that can act as inhibitors. Natural toxins are usually small organic molecules and are so diverse that there are probably natural inhibitors for most metabolic processes.

The metabolic processes targeted by natural poisons encompass more than enzymes in metabolic pathways and can also include the inhibition of receptor, channel and structural protein functions in a cell. For example, paclitaxel (taxol), an organic molecule found in the Pacific yew tree , binds tightly to tubulin dimers and inhibits their assembly into microtubules in the cytoskeleton .

Many natural poisons act as neurotoxins that can cause paralysis leading to death and have functions for defence against predators or in hunting and capturing prey. Some of these natural inhibitors, despite their toxic attributes, are valuable for therapeutic uses at lower doses. An example of a neurotoxin are the glycoalkaloids, from the plant species in the Solanaceae family (includes potato , tomato and eggplant), that are acetylcholinesterase inhibitors. Inhibition of this enzyme causes an uncontrolled increase in the acetylcholine neurotransmitter, muscular paralysis and then death.

Neurotoxicity can also result from the inhibition of receptors; for example, atropine from deadly nightshade ( Atropa belladonna ) that functions as a competitive antagonist of the muscarinic acetylcholine receptors . Although many natural toxins are secondary metabolites, these poisons also include peptides and proteins. An example of a toxic peptide is alpha-amanitin , which is found in relatives of the death cap mushroom. This is a potent enzyme inhibitor, in this case preventing the RNA polymerase II enzyme from transcribing DNA. The algaltoxin microcystin is also a peptide and is an inhibitor of protein phosphatases. This toxin can contaminate water supplies after algal blooms and is a known carcinogen that can also cause acute liver hemorrhage and death at higher doses.

Proteins can also be natural poisons or antinutrients , such as the trypsin inhibitors that are found in some legumes , as shown in the figure above. A less common class of toxins are toxic enzymes: these act as irreversible inhibitors of their target enzymes and work by chemically modifying their substrate enzymes. An example is ricin , an extremely potent protein toxin found in castor oil beans . This enzyme is a glycosidase that inactivates ribosomes. Since ricin is a catalytic irreversible inhibitor, this allows just a single molecule of ricin to kill a cell.

Author: Chandran Nambiar K C

I started practicing homeopathy in 1970, when I was 20 years old and studying for final year of BSc (Zoology) course. My interest in homeopathy happened very accidentally, through a constant relationship with a local practitioner who happened to be father of my classmate. I was a regular visitor in his clinic, where from I started reading BOERICKE MATERIA MEDICA and other homeopathic books, which helped me to cure myself my troublesome asthma that have been haunting me since my childhood days. I became a voracious reader of homeopathy. I was also deeply involved in studying marxism and dialectical materialism during my college days, which attracted me to political activities. MARXISM and HOMEOPATHY became two essential parts of my intellectual and practical life, which still continues so. Even though I joined DHMS course in a karnataka homeopathic college, I could not continue it due to my intense involvement in revolutionary political activities that resulted in jail life and a lot of criminal cases. Once that phase was over, I took a diploma in veterinary science and became a livestock inspector in animal husbandry department under govt of kerala. I have been continuing my study and practice of homeopathy all through these years. Since CCH act came into force only in 1976, and it contained provisions allowing existing practitioners to continue, my homeopathic practice went smoothly in parallel with my government job. In 1987, co-operating with some local homeopaths and social activists, I started Kannur District Homeopathic Hospital Sociey, which established a chain of hospitals and homeopathic clinics in different parts of Kannur district. After a few years I had to leave the society for some political reasons, and I established a 100 bedded well equipped homeopathic hospital in Taliparamba, employing a number of prominent homeopaths. That was ended up as a financial disaster for me due to many reasons, including my lack of skills as a money manager, and I was compelled to close down my dream project with in a short period. I lost huge money I invested, lost my reputation, and it pulled me into a debt trap. I learned a lot of valuabl lessons from this failure- about life, human psychology, relationships, and above all, about myself. I realized failure is the greatest teacher, if you are prepared learn from it. I learned how will power and determination to win will help us come back into life as a phoenix from our own ashes. I learned, one does not fail unless he stops fighting and accepts failure. My failure and the hardships that followed has moulded my personality in such a way that I can now withstand any disaster and fight back. I tell you, you will not know what life really is, unless you miserably fail at least once in your life. By this time, I left my government job also, and settled as a full time homeopathic practitioner. By this practice, I could repair my earlier financial losses, and establish well in life. It was during this period that I felt the need of developing a simple and user-friendly homeopathic software, that resulted in the evolution of SIMILIMUM, which was later upgraded into SIMILIMUM ULTRA. Similimum Ultra was well accepted by the profession, and it collected good revenues which continues even today. I stopped my practice a few years back , and concentrated in the study and research activities to evolve scientifically viable explanations to the so-called riddles of homeopathy. This unrelenting study resulted in MIT or Molecular Imprints Therapeutics, which provides a scientific and rational explanation for homeopathy. I started a homeopathic discussion group on facebook called HOMEOPATHY FOR TOTAL CURE, which has more than 35000 homeopaths as members. By this work on facebook, I could establish close relationship with many homeopaths around the world. It goes on. I could successfully convert facebook as my office and work place, from where I propagate my MIT ideas, co-ordinate my works for homeopathic community, and sell my Similimum Ultra Software. My years of hardwork in search of HOW HOMEOPATHY WORKS ultimately resulted in the publication of a book titled REDEFINING HOMEOPATHY (3000 pages, 3 volumes, hard bound, Rs 6000), in which I have compiled my articles regarding my scientific explanations of basic principles of homeopathy. These ideas are called MIT or MOLECULAR IMPRINTS THERAPEUTICS. MIT is now included in the syllabus of MD (HOM) course of prestigious DY PATIL DEEMED UNIVERSITY, PUNE, INDIA. Research department of SARADA KRISHNA HOMEOPATHIC COLLEGE, Kulashekharam, Tamilnadu, India, the only NAC accredited homeopathy college in India, has recently taken up certain reserch projects for proving the scientific explanations proposed by MIT. Based on MIT perspective of homeopathy, I had developed an MIT PROTOCOL for scientific homeopathy, and initiated a project for establishing a chain of MIT NETWORK CLINICS all over India, where MIT PROTOCOL will be practiced. More over, I have developed a whole range of 351 MIT FORMULATIONS, which are disease-specific combinations of post-avogadro diluted homeopathy drugs. NOW I AM IN 71st YEAR OF MY LIFE, AND STILL LOOKING FOR NEW HORRIZONS!

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