Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction.

@article{citeulike:2422876, abstract = {(-)-Cocaine is a widely abused drug and there is currently no available anti-cocaine therapeutic. Promising agents, such as anti-cocaine catalytic antibodies and high-activity mutants of human butyrylcholinesterase (BChE), for therapeutic treatment of cocaine overdose have been developed through structure-and-mechanism-based design and discovery. In particular, a unique computational design strategy based on the modeling and simulation of the rate-determining transition state has been developed and used to design and discover desirable high-activity mutants of BChE. One of the discovered high-activity mutants of BChE has a approximately 456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the structure-and-mechanism-based design and discovery effort demonstrates that the unique computational design approach based on transition state modeling and simulation is promising for rational enzyme redesign and drug discovery. The general approach of the structure-and-mechanism-based design and discovery may be used to design high-activity mutants of any enzyme or catalytic antibody.}, address = {Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA. zhan@uky.edu.}, author = {Zheng, F. and Zhan, C. G. }, citeulike-article-id = {2422876}, doi = {http://dx.doi.org/10.1039/b716268e}, issn = {1477-0520}, journal = {Org Biomol Chem}, month = {March}, number = {5}, pages = {836--843}, posted-at = {2008-07-24 12:59:57}, priority = {0}, title = {Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction.}, url = {http://dx.doi.org/10.1039/b716268e}, volume = {6}, year = {2008} }

TY - JOUR ID - citeulike:2422876 L3 - citeulike-article-id:2422876 TI - Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction. JF - Org Biomol Chem VL - 6 IS - 5 SP - 836 EP - 843 AD - Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA. zhan@uky.edu. SN - 1477-0520 N2 - (-)-Cocaine is a widely abused drug and there is currently no available anti-cocaine therapeutic. Promising agents, such as anti-cocaine catalytic antibodies and high-activity mutants of human butyrylcholinesterase (BChE), for therapeutic treatment of cocaine overdose have been developed through structure-and-mechanism-based design and discovery. In particular, a unique computational design strategy based on the modeling and simulation of the rate-determining transition state has been developed and used to design and discover desirable high-activity mutants of BChE. One of the discovered high-activity mutants of BChE has a approximately 456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the structure-and-mechanism-based design and discovery effort demonstrates that the unique computational design approach based on transition state modeling and simulation is promising for rational enzyme redesign and drug discovery. The general approach of the structure-and-mechanism-based design and discovery may be used to design high-activity mutants of any enzyme or catalytic antibody. AU - Zheng, F AU - Zhan, CG PY - 2008/03/07/ UR - http://dx.doi.org/10.1039/b716268e ER -