Monthly Publication Highlights Leading-Edge Computational Drug Design


May 06, 2014

A research article showcasing a computationally-designed enzyme which has promise for cocaine detoxification and cocaine-induced lethality is the UK College of Pharmacy Research Publication Highlight for April 2014.

The article was published in Nature Communications and is entitled, “A highly efficient cocaine detoxifying enzyme obtained by computational design.”

The research was conducted in the laboratory of Chang-Guo Zhan, Director of the College’s newly-created Molecular Modeling and Biopharmaceutical Center. The team who worked on the project included Fang Zheng, Associate Professor, Liu Xue and Shurong Hou, graduate students, Junjun Liu, visiting scientist, Max Zhan, research intern, and Wenchao Yang, a visiting scientist with the College.

Compared with naturally occurring enzymes, computationally designed enzymes are usually less efficient, with their catalytic activities being more than 6-orders of magnitude below the diffusion limit of the substrate. However, the Zhan Laboratory has used a two-step computational design approach, followed by experimental work, which led to the discovery of a highly efficient and specific cocaine hydrolyzing enzyme called E30-6 which was derived from human butyrylcholinesterase. The catalytic efficiency of E30-6 for cocaine hydrolysis is comparable to that of the most efficient naturally occurring esterase, i.e., acetylcholinesterase, which metabolizes acetylcholine. Zhan and colleagues further showed that E30-6 protects mice from a subsequently administered lethal dose of cocaine, suggesting that the enzyme may have therapeutic potential for cocaine detoxification.

“E30-6, with catalytic activity comparable to naturally occurring enzymes, also may have efficacy as a therapeutic for cocaine addiction,” said Linda Dwoskin, Associate Dean for Research. “Further, this approach may be useful for the future rational design of a range of biologics for other therapeutic indications.”

page last modified: February 19 2014     

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