Drug discovery and development has historically been a slow and expensive process. The overall costs of successfully developing a single drug entity, from discovery to marketplace are estimated to range from 100 million to 500 million US dollars. For the past 100 years, drugs have been discovered by trial and error. This practise may now yield to deliberate design – thanks to the mapping of the human genome.
The Human Genome Project launched in 1990s jointly by the US Department of Energy and NIH, has helped in mapping the entire human genome, identifying a large number of disease-associated genes and has culminated in the draft sequence of the whole genome. With this information and the application of computer software to determine receptor structure, there has been a revolution in computer aided drug design (CADD). Today new chemical structures are being designed from direct investigation of the size, shape and electrostatic potential of the target receptor site.
The advantages of this approach are:
• Reduction of cost in drug development
• Increased receptor selectivity
• Increased potency
• Reduced side-effects
• Increased patient compliance

The future of drug design: A case study
Researchers decided to find a better
version of the popular class of anti-
hypertensives – ACE (angiotensin converting enzyme) inhibitors with the help of genomics. This need was felt because ACE inhibitors were found to be ineffective in some groups of patients. The first step involved was searching the huge public genome database for snippets of DNA that resembled the known ACE enzyme. From this search 10,000 computer matches were obtained.

Narrowing Choices
The researchers then turned to their library of several million frozen DNA fragments and selected 10,000 snippets corresponding to those computer matches. These were placed in tiny wells on plastic plates and fed to the robot called Zeus. With the help of its quill-like probes Zeus picked up microscopic droplets of DNA and spotted them on a sheet of nylon paper, creating a so-called micro-array. These sheets were rolled up and slipped into test tubes. The test tubes were then washed with genetic material from a wide range of tissue cells labelled with a radioactive dye.
When a gene is active in a particular cell type, the spot lights up under UV. By comparing patterns of brightness, the researchers isolated one gene, which they called ACE-2, that appeared to be particularly active in heart and kidney cells, where high blood pressure could be especially dangerous.

Isolating the Drugs
The next step was looking for a
chemical that would inhibit ACE-
2 and manipulating its chemical structure with the help of protein modelling to give it optimal binding affinity with the ACE–2 receptor.

Testing in Animals
Researchers then tested the ACE-2
inhibitor molecule for safety and
efficacy in laboratory animals. Getting to this point would normally have taken up to 10 years, but with access to the genome database and high throughput machines like Zeus, it took just two years.

Testing in Humans and regulatory approval
Once the safety and efficacy of
ACE-2 inhibitor has been
established in animals, researchers will go ahead with trials on humans. Once the human trials are complete and the ACE-2 inhibitor is shown to be both safe and effective, it will be ready for review by the government regulatory authorities.

Old Diseases, New Approaches
HIV/AIDS
The HIV virus binds with cytokine receptors on CD4 cells. This alters the structure of cell membrane, letting the viral capsid enter the host cell and begin replication. The antiretroviral drugs that are currently used block the virus once it gets into the cell. All currently approved anti-HIV drugs inhibit one of two HIV enzymes, reverse transcriptase (nucleoside analogs and NNRTIs) or protease (protease inhibitors).
Several drugs in the pipeline are aimed at novel targets; most notable are a new class of drugs called fusion inhibitors. Fusion inhibitors bind to a protein on HIV’s surface, called gp41. Once it does this, HIV cannot successfully bind with T-cells, thus preventing the virus from infecting healthy cells. Other new molecules that are being developed are the integrase inhibitors, which interfere with HIV’s ability to insert its genes into a cell’s normal DNA. If the early promise of the fusion inhibitors bears out they will be a welcome and much needed addition to the HIV drug arsenal.

Cancer
Traditional cancer treatments – chemotherapy and radiation affect all fast growing cells, often destroying healthy tissue along with tumours. Researchers are in the process of developing new drugs, which will cause minimal ‘collateral’ damage and trigger relatively few side effects. A new drug, Imatinib disables a uniquely aberrant protein in chronic myelogenous leukaemia. When tested in patients, 30% showed no signs of chromosomal damage and appeared to have been cured. Recently Onyx-015, a virus that infects and specifically kills cancer cells has been developed in the form of injections and in combination with chemotherapy has been found to melt (reduce) tumours in patients with late-stage head and neck cancer.
Other new treatments include monoclonal antibodies (IMC-C225), which prevent a specialised protein known as growth factor (that signals the cancer cells to reproduce), from binding to the surface of the cancer cells. Antibodies are also being drafted to prod the immune system into attacking cancer cells. In the future, traditional chemotherapy will be combined with Cox-2 inhibitors (that force cancer cells to self-destruct) and the so-called antiangiogenic factors, that stop the growth of tumour by arresting the growth of new capillaries.

Obesity
It was the discovery of leptin in 1994 that really set the research in to the genetics of obesity rolling. Leptin is a gene, which controls appetite depending on the fat stores in the body. Administration of leptin to obese mice demonstrated a weight drop by a dramatic 30% within as little as two weeks. However leptin does not remain in the body long enough and trials are underway using a leptin drug with a longer half-life. Leptin triggers the release of a large protein known as pro-opiomelanocortin (POMC), which is broken down into individual peptides, known as melanocyte stimulating hormone (MSH). This in turn binds to a receptor known as MC4, which decreases appetite. Researchers are now discovering that there are genes controlling the production of all these proteins and that damaging any one of them can disrupt the entire process. If doctors could screen the genes of obese people to see which ones are dysfunctional, they could prescribe drugs that stimulate an under-stimulated receptor.
Parkinson’s Disease
Parkinson’s disease is recognised as a progressive neurodegenerative condition caused by a combination of genetic and environmental factors. In case of Parkinson’s, the brain tissue becomes clogged with a protein called alpha-synuclein, which leads to neuron damage, loss of neurotransmitter dopamine and eventually the familiar shakiness of Parkinson’s disease. Parkinson’s patients have to bear with treatments that offer some relief, but not a cure.
Interest in the genetics of Parkinson’s disease has recently escalated with the discovery of mutated alpha synuclein genes and the presence of ‘Parkin gene’ (recessive gene) in Parkinson’s patients. Repairing or replacing nerve cells that have been damaged is as important as protecting healthy neurons. Researchers are developing a new class of drug candidates –(called neuroimmunophillin ligands) that may have the potential to regenerate nerve cells damaged by injury or disease. Other possible treatments include boosting antioxidants to protect brain cells from free radicals and blocking production of excitatory amino acids, which can cause neuron damage. The new-generation drugs developed for Parkinson’s may also be used for treating Huntington’s, Lou Gehrig’s and even Alzheimer’s disease, all of which have similar neurodegenerative roots. It is hard to say which of these treatments will succeed. Millions afflicted by neurodegenerative disease hope that some will potentially slow down, stop or reverse the course of their illness.

FORECAST OR FICTION?
Are we talking science
fiction or would all
these be a reality a few years down the line? While it is difficult to predict what would be possible by when, the fact is that advancements in drug development are taking place at a faster pace than ever before. Pessimists may worry about new disorders and new organisms posing challenges beyond today’s fancy technology. However, as long as ingenuity remains man’s primary weapon, there will always be hope.