A highly efficient cocaine-detoxifying enzyme obtained by computational design

Fang Zheng, Liu Xue, Shurong Hou, Junjun Liu, Max Zhan, Wenchao Yang, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Compared with naturally occurring enzymes, computationally designed enzymes are usually much less efficient, with their catalytic activities being more than six orders of magnitude below the diffusion limit. Here we use a two-step computational design approach, combined with experimental work, to design a highly efficient cocaine hydrolysing enzyme. We engineer E30-6 from human butyrylcholinesterase (BChE), which is specific for cocaine hydrolysis, and obtain a much higher catalytic efficiency for cocaine conversion than for conversion of the natural BChE substrate, acetylcholine (ACh). The catalytic efficiency of E30-6 for cocaine hydrolysis is comparable to that of the most efficient known naturally occurring hydrolytic enzyme, acetylcholinesterase, the catalytic activity of which approaches the diffusion limit. We further show that E30-6 can protect mice from a subsequently administered lethal dose of cocaine, suggesting the enzyme may have therapeutic potential in the setting of cocaine detoxification or cocaine abuse.

Original languageEnglish
Article number3457
JournalNature Communications
StatePublished - Mar 18 2014

Bibliographical note

Funding Information:
This work was supported by the NIH (grants R01 DA035552, R01 DA032910, R01 DA013930, and R01 DA025100 to CGZ). We acknowledge the Computer Centre at the University of Kentucky for supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4,816 processors.

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • General
  • Physics and Astronomy (all)


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