Computational redesign of human butyrylcholinesterase for anticocaine medication

Yongmei Pan, Daquan Gao, Wenchao Yang, Hoon Cho, Guangfu Yang, Hsin Hsiung Tai, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of BChE in the TS1 structure for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W, Y332G BChE should be significantly stronger than that in the TS1 structure for (-)-cocaine hydrolysis catalyzed by the WT BChE and other simulated BChE mutants. Thus, the transition-state simulations predict that A199S/S287G/A328W/Y332G mutant of BChE should have a significantly lower energy barrier for the reaction process and, therefore, a significantly higher catalytic efficiency for (-)-cocaine hydrolysis. The theoretical prediction has been confirmed by wet experimental tests showing an ≈(456 ± 41)-fold improved catalytic efficiency of A199S/S287G/A328W/ Y332G BChE against (-)-cocaine. This is a unique study to design an enzyme mutant based on transition-state simulation. The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery.

Original languageEnglish
Pages (from-to)16656-16661
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
StatePublished - Nov 15 2005


  • Cocaine
  • Enzyme-substrate binding
  • Molecular dynamics
  • Rational design
  • Transition-state stabilization

ASJC Scopus subject areas

  • General


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