Transition Structure of Cocaine

Faith Drickamer, Katherine Vassaur, Mary Frances Vassaur

Purpose of our Project
Scientific Background
Computational Approach
Results
References

Purpose of our Project

Our project was designed to reproduce a transition structure that was discussed in a journal article. Faith was interested in an article in Scientific American about catalytic antibodies. There was an example of a transition structure for cocaine while it was being broken down into ecgonine methyl ester and benzoic acid. We used this example as a basis for our own approximation.

Scientific Background

The hydrolysis of cocaine is a difficult reaction, so some researchers are designing catalytic antibodies to facilitate the breakdown. A catalytic antibody is produced like a normal monoclonal antibody from a single cell line, but in the body it functions as a catalyst for a chemical reaction. The most difficult step is making an antigen to stimulate antibody production. For the hydrolysis of cocaine, a transistion structure must be designed. Then a mimic can be synthesized that has a form very similar to the transition structure. This serves as the antigen, and is introduced into a biological system to stimulate antibody production. Several cell lines can then be cultured, each of which produces a slightly different antibody. These antibodies are screened for reactivity and effectiveness, and then a new mimic can be tried. In the body, the catalytic antibody forces the molecule to go into the transition structure. The receptor on the antibody is in the shape of the transition structure, encouraging the molecule to take on a high-energy configuration. Since the transition structure has very high energy, it spontaneously breaks down into two products. These products do not have any effect on the central nervous system, so they cannot produce the "rush" or "high" of cocaine. The products are benzoic acid and ecgonine methyl ester, which are metabolically inactive. They are gradually cleared from the body, and present no real danger. Thus, a person who had been passively immunized with catalytic antibody would experience almost no effect from taking cocaine. We are approximating the transition structure that would be used to design a mimic. We used information from the World Wide Web as well in designing our transition structure, since many of the researchers working on this problem publish their results on the Web.

Computational Approach

We examined the cocaine molecule, and compared it to the products. The obvious place for hydrolysis to occur is between the benzene ring and the seven carbon group.

The products are ecgonine methyl ester

and benzoic acid.

The oxygen atom between the seven carbon group and the carbon with another double bonded oxygen breaks its bond with the seven carbon group and gains a hydrogen ion. The carbon which it was bonded to gains a hydroxide ion. The catalytic antibody would stress the molecule and lengthen the C - O bond.

Results

We attempted to calculate a transition structure with a lengthened bond and slightly compressed distance from the nitrogen group to the benzene ring, putting more stress on the breaking bond. The molecule below shows the longer C-O bond.

We did not have enough calculation time to finish the transition search for this structure. All of our calculations were done using a semi-empirical basis set, because an ab initio basis set would be too computationally expensive. We also had time constraints that caused us to use the semi-empirical basis set. Our group believes that this transition structure is viable, and we will continue work on it. This structure has higher energy than the optimized molecule, but it may need more refinement.

If you have questions or comments, please send me email! faith@shodor.org

References

Journal Citations: Landry, Donald. "Immunotherapy for Cocaine Addiction." Scientific American. 2:276 (Feb. 1997): 42-45.

Web pages: Sherer, Edward C.; Turner,Gordan M.; et al. "A Semiempirical Transition State Structure for the First Step in the Alkaline Hydrolysis of Cocaine, Comparison between the Transition State Structure, the Phosphonate Monoester Transition State Analog, and a Newly Designed Thiophosphonate Transition State Analog." J. Mol. Model. 2 (1996): p.62-69. Online. Abstract Available: http://science.springer.de/jmm/abstracts/1996/6020062.html "Intramolecular Hydrolysis" Available: http://chem3.lfc.edu/research/intra.html

Personal communication: Robert Gotwals, August 11th-15th, 1997. Cindy McInnis, August 11th-15th, 1997. We would also like to thank Mr. Gotwals personally, as he has been a wonderful instructor to us this week.