Novel Anti-Overdose Drug Studied
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LEXINGTON, Ky. (Sept. 4, 2008) – Devastating bodily harm caused by cocaine
overdose may soon be avoided because of new drug discovery made by University of Kentucky
researchers.
By tweaking a naturally occurring enzyme, Chang-Guo Zhan, professor in the department of pharmaceutical sciences at UK's College of Pharmacy, and his colleagues created a molecule that could flush a cocaine overdose out of the body before it can cause irreparable damage to the body.
Currently, doctors can only try to relieve the symptoms of a cocaine overdose. If the enzyme undergoing research works in humans, it could remove the drug from a user's body.
Enzymes in the body combine cocaine with water and then, over a sequence of reaction steps, break it down into two harmless products. However, this process is very slow – it takes up to 90 minutes to dispose half of even a tiny dose, and much longer for a large overdose. Zhan says that the molecule his team created can break down cocaine much faster.
"Our drug discovery was based on rational design using a novel computational approach," said Zhan.
Zhan and his colleagues, including scientists at the University of Michigan Medical School, calculated the energy required to perform each reaction step, which enabled them to determine how much energy a molecule should have to successfully react. Using computer simulations that systematically tweak the structure of the enzyme and predict the effect of these tweaks on the energy barrier, Zhan and his colleagues arrived at a candidate molecule that promised to speed up the degradation of cocaine by 2,000 times faster than the naturally occurring enzyme. The molecule was then synthesized and tested on animal models to determine whether it might work in the human body.
By tweaking a naturally occurring enzyme, Chang-Guo Zhan, professor in the department of pharmaceutical sciences at UK's College of Pharmacy, and his colleagues created a molecule that could flush a cocaine overdose out of the body before it can cause irreparable damage to the body.
Currently, doctors can only try to relieve the symptoms of a cocaine overdose. If the enzyme undergoing research works in humans, it could remove the drug from a user's body.
Enzymes in the body combine cocaine with water and then, over a sequence of reaction steps, break it down into two harmless products. However, this process is very slow – it takes up to 90 minutes to dispose half of even a tiny dose, and much longer for a large overdose. Zhan says that the molecule his team created can break down cocaine much faster.
"Our drug discovery was based on rational design using a novel computational approach," said Zhan.
Zhan and his colleagues, including scientists at the University of Michigan Medical School, calculated the energy required to perform each reaction step, which enabled them to determine how much energy a molecule should have to successfully react. Using computer simulations that systematically tweak the structure of the enzyme and predict the effect of these tweaks on the energy barrier, Zhan and his colleagues arrived at a candidate molecule that promised to speed up the degradation of cocaine by 2,000 times faster than the naturally occurring enzyme. The molecule was then synthesized and tested on animal models to determine whether it might work in the human body.
Zhan says the overdose therapy should have few side effects in
humans.
“We expect that this candidate molecule can be tolerated very well in the human body because it is a variant of the primary cocaine-metabolizing enzyme in the human body and we have not made any change on the enzyme surface," Zhan said.
Cocaine is a powerfully addictive stimulant drug that has many adverse effects on the body including damage to the central nervous system, the cardiovascular system, respiratory system and digestive system.
“We expect that this candidate molecule can be tolerated very well in the human body because it is a variant of the primary cocaine-metabolizing enzyme in the human body and we have not made any change on the enzyme surface," Zhan said.
Cocaine is a powerfully addictive stimulant drug that has many adverse effects on the body including damage to the central nervous system, the cardiovascular system, respiratory system and digestive system.