In the history of medicine, the hunt for drugs has been an empirical one. Substances from plant, marine and even animal sources have been tried and, over the years, several useful substances have emerged as medications against chosen illnesses as well as for specific medical conditions. More often than not, many of these are general-purpose ones used as tonics, such as gingko biloba or green tea in the Orient, Ashwagandha in Indian Ayurveda, or Zinda Tilismat in the Unani system. But in some ones such as the cinchona bark against malaria, or leaves from the periwinkle plant, used in traditional medicines against cancer, the ‘active’ principles have been confirmed by modern organic chemistry to contain quinine, and vincristine respectively. Yet all these attempts have been empirical, trial and error methods that have taken centurries to grow.
With advances in chemistry, it has become possible to separate individual molecules from such mixtures and synthesise them in pure form in the laboratory — a branch that bears the name natural products chemistry, an area that has been a fertile and focused field in India since the 1950s.
At the same time, advances in the medical sciences, particularly in the field of pathology, have led us to focus on the organ, tissue and cells which are affected and malfunction. And advances in biology have allowed us to get an idea of what has gone wrong at the molecular or cellular level during the malfunction, thus leading to the era of cellular and molecular medicine.
For example, the disorder diabetes is caused by abnormally high levels of sugar in the body. While sugar is essential since it is the fuel for the maintenance and growth of cells and tissue, excess levels of it go to “choke” the metabolism by modifying the chemical structure (and therefore the function) of several proteins’ molecules. One example is the chemical reaction between sugar and the oxygen-transport protein, haemoglobin. This reaction modifies the structure of haemoglobin in a manner that its ability to carry and transport oxygen to cells is affected. Once this choking action had been understood, researchers have developed drug molecules (such as metformin) that level down the production of sugar in the liver to acceptable limits.
Note that the drug that the researcher ‘designs’ should fit the relevant molecules/cell component specifically like a glove on hand or a key on a lock. That way, the specific step(s) are affected without disturbing other components in the cellular machinery in any manner, so that there are no side effects.
It happens occasionally that the “side effects” may not only be harmless, but may prove helpful elsewhere in the body for some other malfunction, purely by happenstance. Aspirin is one such double-action drug. Introduced first as a pain-reliever, it has also been found to help dissolve clotting of blood. Its analgesic action is on the nervous system while its clot-dissolving action is through its action on platelet cells in blood. Aspirin is thus a master key that appears to open more than one lock. And it is not just a single example — there are others.
The molecule termed ELQ 300 is an antimalarial, which acts against the malaria parasite both in the liver stage and when the parasite has already entered the bloodstream as well, making it a double-action drug. Likewise the peptide M5 that Dr Anand Ranganathan has come out with (described in our last column of January 29, 2015, < http://www.thehindu.com/sci-tech/health/building-a-molecular-lego-to-fight-malaria-and-tb/article6830912.ece ), promises to be effective against TB and malaria.
A recent double-positive example comes from the University of Texas Health Science centre. Dr Shapiro and his group there have found that the drug retiganine, used to control convulsion in epilepsy patients, acts also as an effective drug to reduce acute stroke in mice. The group finds that mice affected by stroke, when treated with this anti-epilepsy drug, showed no difficulty in movement, balance and coordination.
Why did the group even try retigabine? “We thought if we could stop the neurons from firing, stopping their electrical activity, we could conserve their resources until the time their blood supply was restored. This proved to be the case”, Dr Shapiro is quoted as saying. . And his coworker Dr Bierbower says: “It is treating the first step in the sequence and stopping the more damaging secondary effects. These agents (like retigabine) directly affect the nerve cells themselves.”
With increasing knowledge gained about the detailed shape and architecture of proteins and other biopolymer molecules in the cell (the ‘locks”), and their computer-based modelling on one hand, and the electrophysiological steps on the other, the field of ‘in silico” or computer-projection and representation of the cellular players has become possible. This allows us to look for drug molecules (the keys) that fit in like Lego pieces — the possibility of finding more than one “ lock” increases and the number of double action drugs’ promises ( even triple-action ones) will be on the rise. The ‘vaidya’ or medicine man has now become the computer-savvy drug designer.
The old trial and error is modernised into “high throughput screening” of hundreds of molecules, and the time for ‘bingo’ here is in days rather than years. But the principle is quite the same. As the French have it: Plus ça change, plus c'est la même chose, or “the more things change, the more they stay the same.”
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