Design of new molecules having desired properties is an important consideration in the development and growth of pharmaceutical industries. Design of new molecules is a difficult problem not only in pharmaceutical industries but also in chemical industries and material science. One can approach this problem by an iterative formulation, synthesis, and evaluation cycle. The third step is long, time-consuming and expensive. Molecular and mathematical modelling with current computer-aided design approaches includes heuristic and exhaustive searches, and knowledge-based systems methods help in reducing time and money. Recently, a genetic algorithm-based approach has been shown to be quite promising in handling these difficulties. In this paper, we present some recently developed molecules in the field of pharmaceutical industries and their applications.

A novel lipid molecule
Scientists at UC Santa Barbara have created a new molecule that delivers therapeutic genes directly to cells. It promises to fight disease with gene therapy. Inherited diseases, as well as many cancers and cardiovascular diseases, may eventually be treated by such an approach. Therapeutic genes can correct genetic defects, for example, or help the body's immune system fight cancer cells.

For more than two decades, gene delivery has been accomplished by using engineered viruses as a vehicle to get into diseased cells, and 70 per cent of such clinical trials worldwide continue to use this method. But the viruses used for gene delivery occasionally evoke severe immune responses, so scientists continue to search for non-viral delivery vehicles.

Lipids are molecules with two parts: a water-liking "head group" and oily tails that assemble together to avoid water. Lipids, along with carbohydrates and proteins, constitute the main structural material of living cells.

Lipid DNA complexes are attracting increasing attention as non-viral DNA delivery vehicles. They have been described as one of the "hottest new technologies" for gene therapy, accounting for nearly 10 per cent of ongoing clinical trials.

The novel lipid molecule created at UC Santa Barbara has a tree-shaped, nanoscale head group and displays unexpectedly superior DNA-delivery properties. "It generates a honeycomb phase of lipid DNA complexes," said Cyrus R. Safinya, professor of materials, physics, and of molecular, cellular and developmental biology at UCSB. The new molecule was synthesized in Safinya's laboratory by first author synthetic chemist Kai K. Ewert, who is a project scientist in the research group.

The structure of lipid DNA complexes strongly affects their ability to deliver DNA. "Complexes containing sheets or tubes of lipids have been known since Safinya's group found these structures in 1997 and 1998, but no one had ever seen nanoscale cylinders such as the ones in our honeycomb lattice," Ewert said. The scientists proved the formation of this novel structure with X-ray scattering experiments. Ewert designed and synthesized the new lipid by manipulating the size, shape, and charge of a series of molecules. He explained that the new lipid molecule has 16 positive charges in its tree-shaped head group, the largest number by far among molecules in the field of gene delivery.

New molecules by transfection
The process of delivering a gene of interest into the cell is known as "transfection". Two of these are mouse cell lines and two are human cell lines. The honeycomb structure turned out to be highly effective. Ewert developed new gene carrier, which shows superior transfection efficiency compared to commercially available carriers. The most surprising result was obtained with the mouse embryonic fibroblast cells, known as MEFs. These are empirically known to be extremely hard to transfect.

Safinya added: "Our data confirm that the new molecule is far superior for transfection of these cells as compared to commercial lipids." Other co-authors are Safinya's graduate students Alexandra Zidovska, Nate Bouxsein, Ayesha Ahmad, and Heather Evans.

New molecule in ALS therapy
Just a few months ago, Packard Center scientists reported that a new molecule they've designed can counter harmful excitotoxicity. It is still early and the compound is still in animal studies. It has already been prescribed for some other disease and, thus, already safe in patients. So, should it continue to slide down the pipeline, it would still face broad clinical trials. But the fact that GPI-1046 mimics a natural molecule in the body, one that protects nerves and nurtures nerve cell growth, and that it can reverse a well-known step in ALS's downhill path makes it worth watching.

One hallmark of ALS is the surge of glutamate. Normally a fleeting chemical released in small amounts - just enough to hit a target nerve cell and send a message - glutamate in excess is a liability. In ALS and some other neurological diseases, glutamate pools in the synaptic spaces that separate nerve cells. The flood of it overstimulates the chemical's target receptors in nerve cell membranes. Their jangled activity, in turn, trips a harmful biochemical cascade in the cells - excitotoxicity - long suggested as a key cause of motor neuron death in ALS.

Normally, glutamate is cleared from synapses by the nervous system's astrocytes, cells well-stocked with molecules called glutamate transporters which act like sponges. But earlier studies by Jeffrey Rothstein, Packard Center director, showed that both ALS patients and animal models of the disease lose glutamate transporters, with drastic results.

According to Rothstein, who lead the research team, the molecule is a designer version of a brain immunophilin protein. Molecules in that family support neuron survival and, in some situations, promote growth. "We've followed others' studies that describe immunophilins' ability to enhance nerve growth, as well as their usefulness a Parkinson's disease therapy," he says. "Based on good signs there, we thought we should look into them for ALS." So recently, Rothstein, Scottish collaborator Mandy Jackson, fellow Packard scientist Nicholas Maragakis and other Johns Hopkins colleagues studied GPI-1046's effects in cell cultures, spinal cord models and live rodents.

In the first experiments, the drug was applied to rodent spinal cords kept alive in culture. After two weeks, the glutamate transporters in spinal cord astrocytes more than doubled. Later work with spinal cords (now ground-up for ease of study) showed a 50 per cent increase in actual glutamate uptake - a sure sign of transporters at work.

Studies in living rodents kept up the trend: given orally to adult male mice, GPI-1046 increased glutamate transporters by 300 per cent in three weeks. When infused directly into rat brains, the molecule also created a jump in transporter protein there.

Even more telling was the molecule's activity in situations mimicking disease. When a chemical that trips excitotoxicity was introduced into the rodent spinal cord cultures, GPI-1046 protected neurons there in a dose-dependent way, that is, the more drug added, the greater the protection. In the SOD1 mice most often used as models of ALS, oral GPI-1046 increased survival, though modestly.

"The neuroprotection we saw in cultures seems to carry over to live animal models," Rothstein explains. And though the way this neuroimmunophilin works isn't yet clear, he says, "it certainly warrants keeping in the pipeline as a possible way to block the damage from the excitotoxicity that's a cellular threat in ALS."

The above study was carried out by Raquelli Ganel Tony Ho, Mandy Jackson and Joseph Steiner at the Robert Packard Center for ALS Research, from the NIH and the Muscular Dystrophy Association.

New molecule for faster TB cure
Indian researchers have discovered a new molecule that they say could lead to a faster cure for tuberculosis (TB). They have applied for clearance to perform human clinical trials on the potential drug and for patents both in India and in the United States.

The molecule has been tested in rats and in guinea pigs, where it reduced the normal treatment time of six to eight months to just two months. In addition, it was found to be effective against all known drug-resistant strains of the bacterium that causes TB.
Indian science minister Kapil Sibal announced the results on 6th September 2006. Dr Mashelkar, director general of the Council of Scientific and Industrial Research (CSIR), which participated in the study, says this is the first time in 40 years that a TB drug candidate has shown promising results in animal studies.

Mumbai-based Lupin Laboratories identified the new molecule in 2001. In subsequent cell-based and animal studies, researchers found that it significantly reduced numbers of TB bacteria. When given in combination with other TB drugs, it cleared TB bacteria in animal lungs and spleens within two months. Over the course of six months, the scientists found no evidence that the bacteria developed resistance to the drug. The researchers observed no adverse effects on tested animals whether the molecule was given in single or multiple doses, and a single oral dose given daily was effective.

The proposed human trials would study whether the molecule could work as a stand-alone drug, or substitute one or two components of the present four-drug cocktail, says Sudarshan Arora, of Lupin Laboratories. The current anti-TB treatment lasts six to eight months and is effective only in an uninterrupted schedule. In many resource-poor countries, patients often skip their doses, which make multiple drug resistance more likely. Some 1.6 billion people (almost one-third of the world population) are infected with TB, with eight million new cases occurring each year. The current global market for TB drugs is estimated at US$ 600 million.

A consortium of 12 government research institutes and universities joined Lupin Laboratories to develop the molecule. They included three CSIR laboratories: the Central Drug Research Institute in Lucknow, the Indian Institute of Chemical Technology in Hyderabad, the National Chemical Laboratory in Pune, and the University of Hyderabad.

HIV stymied by new molecule
The much-celebrated advances made last year in understanding how HIV wangles its way into cells have led to the discovery of what may be a new way to thwart the virus. In last week's issue of Science, researchers describe a molecule, modified from a naturally occurring immune messenger, that seems exceptionally capable of preventing HIV from entering uninfected cells - at least in the test tube.

The work builds on a flood of findings published last year that linked HIV and chemokines, the family of inflammation-promoting chemicals to which the new molecule, called AOP-RANTES, belongs. Researchers have known for more than a decade that HIV slips into white blood cells using a receptor found on their surface known as CD4, but it appeared to need some other co-receptor, too. Last year, the missing player turned out to be the cell-surface molecules that normally serve as receptors for chemokines. Since then, many researchers have begun exploring ways to prevent HIV infection by blocking chemokine receptors.

While some AIDS researchers believe that injections of chemokines themselves may safely block HIV infection, others worry that such treatments might cause severe inflammation. To get around this possible side effect, a team of researchers from the Chester Beatty Laboratories in London, the Geneva division of drugmaker Glaxo Wellcome, and the Laboratory for Molecular Pharmacology in Copenhagen have modified the chemokine RANTES so that it can bind to the receptor without triggering an inflammatory response.

The new molecule appears to have much more potent anti-HIV powers than does RANTES - which itself has the most potent anti-HIV affects of any natural chemokine - by tying up more receptors. "This particular compound is a stronger inhibitor than anything [similar] shown so far," says Robin Weiss, who heads the lab at Chester Beatty in which several of the paper's co-authors work. What's more, AOP-RANTES works both in immune cells known as T cells and in macrophages, whereas RANTES only works in T cells.

Experts in the field are reacting with guarded optimism. "What they found may well be a pretty good drug - if they can keep levels high enough in the body for 24 hours a day, 7 days a week," says chemokine researcher Craig Gerard of Harvard University. That, of course, has proven to be an insurmountable "if" for many other promising compounds. Even Weiss, whose lab has been fielding media calls all day, worries that the work "is being hyped up too much."

New molecule to eradicate cancer
Researchers at Yale University have developed a new molecule they call "icon" that targets blood vessels in tumours for destruction by the immune system without harming vessels in normal tissues.

"Our study resulted in the eradication of injected tumours and also of other tumours in mice that had not been injected," said principal investigator Alan Garen, professor of molecular biophysics and biochemistry at Yale University. "This serves as a model of metastatic cancer. None of the normal tissues in the mouse appeared to be harmed by our procedure."

Published in the October 9 issue of Proceedings of the National Academy of Sciences, the study was conducted with human melanoma and prostate tumours growing in mice. The gene for the icon was inserted into an adenovirus vector that was injected into a tumour, resulting in the infection of tumour cells that act within the mice as factories for producing the icon and secreting it into the blood.

Garen said that in order to target tumour blood vessels without harming the normal blood vessels, a molecule that is expressed specifically on the inner surface of the tumour is needed. The molecule used for this study is called tissue factor, whose normal function is to initiate blood clotting.

Blood clotting occurs when another molecule called factor VII, which circulates constantly in the blood, binds to tissue factor. The binding of factor VII to tissue factor is one of the strongest and most specific interactions known in biology. Garen and Yale research scientist Zhiwei Hu, constructed the icon, which is modelled after a camel's version of an antibody. The icon is composed of two parts. One part targets the icon to tissue factor by using factor VII as the targeting domain. The other part of the icon is the region of a natural antibody that activates an attack by the immune system against cells that bind to the icon.
"The result is that the tumour blood vessels are destroyed by the immune system and consequently the tumour cells die because they lack a blood supply," said Garen. "The normal blood vessels survive because they do not express tissue factor and therefore do not bind the icon."

"This icon should work against all types of tumours that contain blood vessels," said Garen. "The icon that will be used in a clinical trial is derived entirely from human components and therefore should not be significantly immunogenic, which is an advantage over antibodies used in this kind of study." Garen said the procedure could also be effective against other diseases that require growing blood vessels, such as macular degeneration, the major cause of blindness in older people. A clinical trial is being arranged by Albert Deisseroth, M.D., formerly of Yale University, and currently President of the Sidney Kimmel Cancer Center in San Diego.
E-mail: pa_mandal@yahoo.co.in