Off the Wire:
UD researchers on leading edge of molecular design
John T. Koh, associate professor of chemistry and biochemistry, directs a team that is currently working to create hormone analogs that will work more efficiently with mutated forms of receptors that otherwise cause genetic disease.
Their efforts were noted in the Dec. 16 issue of Chemical & Engineering News, a publication of the American Chemical Society, as among the leading biochemistry research developments of 2002.
We have a tremendous amount of information about the biology and chemical structure of hormones and their receptors, Koh said. Because of that, we can use computer models to see how they normally work and how they dont work when they contain mutations. Using these models, we can design new hormones that restore normal function to these otherwise defective receptors.
The group is focusing on Vitamin D, which, despite the name, is a hormone.
Koh said a small number of persons worldwide suffer from a debilitating and ultimately fatal disease called Vitamin D Resistant Rickets (VDRR), in which a mutated gene causes a dysfunctional Vitamin D receptor.
Rickets is a disease caused by a Vitamin D deficiency that leads to a grave thinning of the bones. One relatively benign form can be cured by proper diet and exposure to sunlight or by taking Vitamin D directly. The form that is the result of a genetic defect to the receptor, however, cannot be treated by these methods. VDRR can be very severe and often patients who suffer with it do not reach adulthood.
Koh likened the root cause of VDRR disease to a molecular lock and key that regulates gene expression. Vitamin D is the key but for VDRR patients, the key will no longer fit into their lock because the lock is defective.
If we can understand the structure, we can engineer and create a hormone analog that will match the defective receptor, Koh said. In other words, the researchers can design a new key that will fit the defective lock. This technique differs from gene therapy, in which the gene that forms the lock would be modified to accept the key.
In laboratory efforts to design a working key, Koh and graduate student Steven Swann, who he said is vital to the work, have seen fantastic results.
We have developed compounds that show really dramatic activity at the cellular level, Koh said, with a note of caution, however, as the laboratory findings have not yet been applied to human beings.
The distinctly multidisciplinary Koh group, which includes both graduate and undergraduate researchers, is working in collaboration with a biological research team headed by UDs Mary C. Farach-Carson because there are two forms of Vitamin D receptors, one nuclear and one a membrane.
We are collaborating with her group to evaluate compounds in the membrane receptor, Koh said. If a compound can turn on the nuclear Vitamin D receptor but creates problems with the membrane receptor, it would be of no benefit to the patient. We are trying to create selective solutions that can solve problems while at the same time not creating adverse side effects.
In the long run, Koh said, the research is exciting because many genetic diseases are fairly rare, and there is no economy of scale to entice large pharmaceutical companies to develop drugs to provide a cure.
It costs hundreds of millions of dollars to develop drugs and you cant do that for a small population, Koh said. Through this method, we can use computers to help do the work more efficiently. If effective, it may enable the development of drugs for small patient populations.
Such science is made possible by exponential leaps in knowledge and technology over the last two decades, Koh said. We can understand the biology at the molecular level. It is to the point that we can see the atomic level structure of many biological systems, and that is pretty remarkable.
By zooming in at the atomic level and gaining an understanding of how a genetic structure is defective, Koh said scientists can design molecules to compensate for certain molecular defects.
With the computer, you can make a model and predict how the compound will be used in the receptor, how you can modify to fit the lock, Koh said. That is called virtual screening, which is a hot term at the moment. You can make and evaluate molecules on the computer, select the best candidates to actually create in the laboratory, then measure their biological activities.
Koh said the advances in high-resolution structural biology drew him, as a chemist, to the field. To be honest, I was seduced by the elegance of the molecular structures, he said. This presents an opportunity for chemistry to make a difference in biology. Chemists need to be able to see structures, and once we could do that, we can contribute to the field with our ability to make and manipulate molecular structures.
Today, we can often take a clinical disorder and relate it to a problem at the molecular level and in some cases we may be able to do something about it. It is really exciting, Koh said. This would boggle the minds of people 100 years ago, or even 20 years ago.
In addition to working with Farach-Carson and graduate student Joel Bergh from her group, Koh said his own research team was developed as a multidisciplinary unit so that it has expertise in computer-aided molecular design, chemical synthesis and molecular and cell biology.
Koh said Swann has made a huge contribution to the research, conducting work in computer design and chemical synthesis. He also performed much of the molecular and cell biology used to evaluate the compounds.
Swann is a member of the Chemistry and Biology Interface program, a National Institutes of Health-supported program designed to train a new generation of scientists to work across traditional boundaries.
We and NIH recognized that the next generation of chemists and biologists will need to be able to better communicate and assimilate their ideas, Koh said. Steve represents an ideal example of cross-disciplinary training.
Swann was assisted by Cory Ocasio, an undergraduate researcher who is now in graduate school studying chemical biology at the University of California at San Francisco.
Ocasio was part of UDs McNair Scholars program, designed to prepare low-income, first generation and underrepresented college students for doctoral study.
Contact: Neil F. Thomas, (302) 831-5408
Feb. 26, 2002