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At the Emory University School of Medicine, a compound named Noscapine was discovered (Ye 1601). What started as an attempt to complete an assignment by a graduate student led to a discovery that is astounding.
Keqiang Ye, a new graduate student from China majored in organic chemistry, was given an assignment to look over papers on anti-microtubule drugs by Dr. Harish Joshi, a cell biology professor at Emory University School of Medicine.
Microtubules play a significant role in the division of the cells. Anti-microtubule drugs disturb the assembly of the microtubules and thus prevent the cell from dividing. They are used to destroy cancer cells.
Later discussions between Ye and Joshi led them to believe that there might be compounds out there that are good candidates for anti-microtubule drugs which have already been made and are ready to be purchased. If such compounds existed, much money and time would be saved since no new compounds needed to be synthesized. The task of finding the compound that best shares the characteristics of anti-microtubule drug was given to Ye. After many days of patiently shifting through pages of small prints of compounds in a large directory of chemical compounds, Ye came up with a set of compounds. One of the compounds was Noscapine, a common cough suppressant.
Studies on Noscapine by the scientists at Emory University led to some very promising findings. With Noscapine, they were able to reduce the tumor that had grown from the injection of human breast cancer cells in lab mice by 80 percent after three weeks (Ye 1604). In addition, Noscapine doesn’t have any major side effects, and it is water soluble. This means that Noscapine can be taken in the form of pills instead of going through procedures that infuse non-soluble drugs into the blood stream.
Over at the Modeling Division of Dr. Dennis Liotta’s group at the Chemistry Department, Emory University, the news of Noscapine brought by Dr. Joshi ignited immediate enthusiasm. Under the supervision of Dr. James P. Snyder in Dr. Liotta’s group, the author and Jim Nettles conducted a computer-aided database search for the compounds that shared the characteristics of Noscapine.
Before any search is submitted to a computer, the user must tell the computer what type of compounds to look for.
One of the nice features about using a computer to do the search is that it can sort the compounds that it found in the order from most likely desired compounds to less likely ones.
The size of the database available to the group is quite large. Currently, there are five databases, each one containing around 50,000 chemical structures. One of the databases even contains approximately 100,000 compounds. Another database that contains all the drugs that have been made in the world is soon to be accessed.
The database searching can be generally divided into 2D and 3D searches. 2D search is much faster than 3D search since the former has to look only at the “finger print” of each compound, which lists the characteristics of a compound in binary format. 3D search, on the other hand, involves considering the position of every individual atom in the compound and deciding whether their positions match the query.
The 2D search is first conducted as an elimination process. By performing the 2D search first, the size of compounds from which to choose the Noscapine like compound is reduced greatly in very short time. (Currently, with the available computing power, a database containing 50,000 compounds can be 2D searched within an hour.) Later 3D search is performed to fine-tune the results. Currently we are at the stage just before purchasing a list of chemical compounds and then testing them, which would require a close collaboration among biologists, chemists, clinicians and toxicologists, as Dr. Harish Joshi had envisioned.
Work Cited
- Keqiang Ye, Yong Ke, Nagalashmi Keshava, John Shanks, Judith A. Kapp, Rajeshwar R.Tekmal, John Petros, and harish C. Joshi. Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. Proc. Natl. Acad. Sci. USA. Vol. 95, pp. 1601-1606, February 1998.
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