Most efficient cocaine hydrolase designed by virtual screening of transition states

Fang Zheng, Wenchao Yang, Mei Chuan Ko, Junjun Liu, Hoon Cho, Daquan Gao, Min Tong, Hsin Hsiung Tai, James H. Woods, Chang Guo Zhan

Resultado de la investigación: Articlerevisión exhaustiva

160 Citas (Scopus)


Cocaine is recognized as the most reinforcing of all drugs of abuse. There is no anticocaine medication available. The disastrous medical and social consequences of cocaine addiction have made the development of an anticocaine medication a high priority. It has been recognized that an ideal anticocaine medication is one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., cocaine hydrolysis catalyzed by plasma enzyme butyrylcholinesterase (BChE). However, wild-type BChE has a low catalytic efficiency against the abused cocaine. Design of a high-activity enzyme mutant is extremely challenging, particularly when the chemical reaction process is rate-determining for the enzymatic reaction. Here we report the design and discovery of a high-activity mutant of human BChE by using a novel, systematic computational design approach based on transition-state simulations and activation energy calculations. The novel computational design approach has led to discovery of the most efficient cocaine hydrolase, i.e., a human BChE mutant with an ∼2000-fold improved catalytic efficiency, promising for therapeutic treatment of cocaine overdose and addiction as an exogenous enzyme in human. The encouraging discovery resulted from the computational design not only provides a promising anticocaine medication but also demonstrates that the novel, generally applicable computational design approach is promising for rational enzyme redesign and drug discovery.

Idioma originalEnglish (US)
Páginas (desde-hasta)12148-12155
Número de páginas8
PublicaciónJournal of the American Chemical Society
EstadoPublished - sept 10 2008
Publicado de forma externa

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


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