|
|
|
Once upon a molecule...
SEVERAL thousand years ago when diseases started bothering man, he consciously or unconsciously started treating them even though he was light years from any kind of civilization. In those primitive days, he found remedies in such mundane objects as common plants and worms.
This trend continued for thousands of years, perhaps until the 17th century. Later, when he learnt about the normal and abnormal functioning of the human body he started using specific herbs for treatment. Some substances cured him while others did not.
With repeated attempts or experimentations, a sort of therapeutic system came into existence which grew with time. Some ancient drugs, such as digitalis, opiates and aspirin obtained from foxglove, poppies and barks of willow trees, perhaps, come from the same experiments and are considered useful drugs today.
Even now about 50 to 60 per cent of the drugs are based on compounds coming from the Mother Nature’s pharmamentarium. But it is difficult to trace as to when pure chemicals, such as alkaloids, and various forms of biochemicals, such as enzymes, vitamins and hormones, were considered potential drugs. As science progressed, many therapeutic systems came into being. The most successful one was based on chemical and biochemical compounds.
These compounds are synthesized according to their three-dimensional structures, reaction sites a molecule possesses and the receptors in which it will fit. This is an important issue in drug designing and drug receptor interactions. Most traditional medicines are molecular in the sense that they are synthesized on one or more molecules. But any such medicine has never been found equally effective for all the patients.
This could be due to the fact, that sometimes the manifestation of symptoms of a disease are different in different people. This keeps doctors guessing. They tend to think that the efficacy of a drug varies from person to person due to differences in age, gender, general health, environment and the quality of drugs.
Some important aspects that should be considered while designing chemical or biochemical compounds as drug are as follows: racemic (enantiomorphism) and chirality of the compound; receptor/sites; target orientation, and; genomic or molecular designing.
Racemic and chirality
A drug molecule that contains an asymmetric centre and is capable of occurring in two or more racemic forms is termed a chiral molecule. Many pharmaceutical substances are marketed that contain one or more chiral centres. These are called racemic — a compound converted from an optically active form into an optically inactive one from which half of the optically active substance becomes non-superimposable mirror image or an enantiomer. These exhibit little of the known biological activities of the separate isomers.
In substances containing single chiral centres, optical isomers take the descriptor “RS.” Here R, standing for the Latin word “Rectus,” means “right” and L, short for the Latin word “Sinister,” means “left.” This indicates the rotation of plane polarized light to the right or left. It involves viewing different substituent atoms around each asymmetric carbon atom of the drug in order of decreasing atomic numbers or valence densities.
If the decreasing rank order is clock-wise, the configuration around this chiral centre will be called descriptor R. If the decreasing rank order is anti-clockwise, the configuration is called descriptor S. For substances containing multiple chiral centers and comprising mixtures of all possible stereo isomers or enantiomers the term “all-rac” is used.
Standard Pharmacopoeia have mentioned these descriptors but have not mentioned their usefulness. For instance, ephedrine, a bronchodilator, is 1R, 2S, in which NCH3 and OH are beta-bonded with a specific optical rotation of 33.5 to -35.5. Pseudoephederine, a nasal decongestant, is 1S, 2S in which NCH3 and OH groups are alpha-bonded with specific optical rotation +61.0 to +62.5, whereas its enantiomer Racephedrine, a beta adrenoceptor agonist, is 1RS, 2SR in which OH is beta-bonded while NCH3 is alpha-bonded with a specific optical rotation +0.2 to -0.2.
The generic names and identification tests for all compounds are similar. The first two compounds are frequently used in cough syrups. Most of the time they remain ineffective, that is, neither pseudoephederine improves nasal congestion, nor ephedrine acts as a bronchodilator. Instead, they often exhibit profound differences in pharmacology and toxicology, owing to their racemic nature and/or intermingling, due to carelessness during manufacturing.
As a result, patients suffer. In frustration they blame doctors, as well as manufacturers. Many compounds from natural sources, such as amino acids, alkaloids, antibiotics, glycosides and sugars, exist as chiral compounds. Identification of such compounds can be carried out through chiral chromatography but this has not been included in any pharmacopoeia.
Receptor/site
Receptors play a very important role in drug designing vis-à-vis the functional group of the drug molecule. The concept of categorizing drug action in terms of receptors is of pivotal importance in pharmacology. It is said that receptor does for pharmacology what the periodic table does for chemistry.
The pharmacological activity of a chemical compound depends mainly on its interaction with biological matrices (drug targets) —such as protein (receptors and enzymes), nucleic acids (RNA and DNA) and cell membranes which consist of phospholipids and glyco-lipids. All these compounds have complex 3-dimensional structures, capable of recognizing specific receptor in one of the many possible arrangements in 3-D space.
It is this that determines which potential drug candidate molecules can fit within the cavity of the receptor and with what affinity. Factors that control the 3-D shape of a drug are studied from the perspective of their interaction with potential biochemical targets.
The designing is taken up accordingly. An understanding about how a drug is designed on a chiral molecule, showing its interaction with drug targets, is necessary before marketing.
Target orientation
The importance of most factors affecting the 3-D shape of the drug and receptor depends, in large measure, on designing the drug in such a manner that atoms are separated from each other by a certain distance called bond length and angle. They should be endowed with a certain charge due to bond polarity or hydrophobicity (a property of repelling water) and should feature more rigid fragments such as bonds with partial double bond characters.
Organic structure factors, such as configuration (orientation of the functional group) and conformation (rotation about the single bond), are important in determining the biological activities in compounds of identical or analogous constitution. How drug chirality affects their mode of activity are also considered significant steps in designing a drug.
It is, therefore, necessary that while designing a drug, consideration is given to the shape and size of the molecule which may allow fitting into the binding site of the receptor of target organ in the body and/or surface of the bacteria. Once a drug designer knows this, he can use it as a base to build his drug.
Methylation, carboxylation, substitution or making adducts with appropriate organic or inorganic substances are also important aspects of drug designing as these can alter the action of a drug.
These reactions are usually carried out with the aim of inhibiting enzymes, which viruses or bacteria produce for their replication in an effort to become infective agents.
Drug designing is a very lucrative industry. Almost everyone has health problems. These could be simple like the common cold or could be complex such as cancer. No matter how big or small the problem, every patient longs for a way to alleviate it.
This is what keeps the drug designers going. They work tirelessly for years in search of the right compound — something which could help lessen the pain and agony. Many barriers stand in the way of these professionals but they, more often than not, remain steadfast in their mission.
Genomic/molecular drug designing
The molecular designing of drugs for specific purposes, such as DNA-binding and enzyme inhibition, is based on the knowledge of molecular properties of receptor/site, functional groups and molecular geometry. The human genome project, which has identified three billion nucleotide bases in the human DNA, is giving clues to thousands about new targets for drug development.
Drugs developed after understanding the nature of molecules have revolutionized pharmaceutical industries all over the world. The mystery over why a drug acts as a lifesaver for one person while becoming poisonous for another has been been solved with the help of genetic variants.
It remains to be seen conclusively whether the drugs developed by adopting genomic technology would be devoid of side or adverse effects or not. However, in my opinion, they will become fairly safe in due course.
Current scenario
With the advent of genome mapping — the twisted double strand of DNA, whose structural logic dictates the functional logic of heredity — drug designing has radically been changed. Trial and error with which medicines have been discovered over the past 100 years, and for millenniums before that, are on the verge of extinction.
Modern drugs are now developed and designed by biochemists all over the world employing genes (DNA) of defined sequences to identify the individual molecules that could attack a particular disease. With the help of that information and high-speed silicon-age machinery biochemists have been designing new molecules that approach their targets like a well-aimed arrow.
These molecules are expected to have fewer side-effects than traditional drugs. The side-effects, usually lethal, are often due to the drugs’ non-targeted and non-specific nature.
Francis Collins of the Human Genome Research Institute says: “If you understand the genetic basis of a disease then you can predict what protein it produces and start designing a drug to block it.” With this idea in mind, a good blood pressure drug has been designed by improving a popular Angiotensin Converting Enzyme (ACE) inhibitor.
In short, genomic data is a major source for discovery and development of new therapeutic and diagnostic products by pharmaceutical and biotechnology industries. More than 50 per cent of the drugs currently under clinical trials in the US have been developed using this approach.
The writer
|
|
|
|
