Reaction pathway for cocaine hydrolase-catalyzed hydrolysis of (+)-cocaine

Yuan Yao, Junjun Liu, Fang Zheng, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


A recently designed and discovered cocaine hydrolase (CocH), engineered from human butyrylcholinesterase, has been proven promising as a novel enzyme therapy for treatment of cocaine overdose and addiction because it is highly efficient in catalyzing hydrolysis of naturally occurring (−)-cocaine. It has been known that the CocH also has a high catalytic efficiency against (+)-cocaine, a synthetic enantiomer of cocaine. Reaction pathway and the corresponding free energy profile for the CocH-catalyzed hydrolysis of (+)-cocaine have been determined, in the present study, by performing first-principles pseudobond quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations. According to the QM/MM-FE results, the catalytic hydrolysis process is initiated by the nucleophilic attack on carbonyl carbon of (−)-cocaine benzoyl ester via hydroxyl oxygen of S198 side chain, and the second reaction step (i.e., dissociation of benzoyl ester) is rate-determining. This finding for CocH-catalyzed hydrolysis of (+)-cocaine is remarkably different from that for the (+)-cocaine hydrolysis catalyzed by bacterial cocaine esterase in which the first reaction step of the deacylation is associated with the highest free energy barrier (~17.9 kcal/mol). The overall free energy barrier (~16.0 kcal/mol) calculated for the acylation stage of CocH-catalyzed hydrolysis of (+)-cocaine is in good agreement with the experimental free energy barrier of ~14.5 kcal/mol derived from the experimental kinetic data.

Original languageEnglish
Article number15
Pages (from-to)1-9
Number of pages9
JournalTheoretical Chemistry Accounts
Issue number1
StatePublished - Jan 1 2016

Bibliographical note

Funding Information:
This work was supported in part by the NIH (Grants R01 DA035552, R01 DA013930, R01 DA032910, and R01 DA025100), NSF (Grant CHE-1111761), and NSFC (Grant No. 21102050). The entire research was performed at the University of Kentucky. The authors acknowledge the Center for Computational Sciences (CCS) at University of Kentucky for supercomputing time on IBM X-series Cluster with 340 nodes or 1360 processors.

Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.


  • Catalytic mechanism
  • Cocaine
  • Enzymatic hydrolysis

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry


Dive into the research topics of 'Reaction pathway for cocaine hydrolase-catalyzed hydrolysis of (+)-cocaine'. Together they form a unique fingerprint.

Cite this