Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
2008-08-15
2010-06-08
Saidha, Tekchand (Department: 1652)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C435S196000, C435S197000
Reexamination Certificate
active
07731957
ABSTRACT:
A novel computational method and generation of mutant butyrylcholinesterase for cocaine hydrolysis is provided. The method includes molecular modeling a possible BChE mutant and conducting molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations thereby providing a screening method of possible BChE mutants by predicting which mutant will lead to a more stable transition state for a rate determining step. Site-directed mutagenesis, protein expression, and protein activity is conducted for mutants determined computationally as being good candidates for possible BChE mutants, i.e., ones predicted to have higher catalytic efficiency as compared with wild-type BChE. In addition, mutants A199S/A328W/Y332G, A199S/F227A/A328W/Y332G, A199S/S287G/A328W/Y332G, A199S/F227A/S287G/A328W/Y332G, and A199S/F227A/S287G/A328W/E441D all have enhanced catalytic efficiency for (−)-cocaine compared with wild-type BChE.
REFERENCES:
patent: 7049121 (2006-05-01), Watkins et al.
patent: 2003/0153062 (2003-08-01), Watkins et al.
patent: 2004/0120939 (2004-06-01), Watkins et al.
Gao, et al.; Modeling effects of oxyanion hole on the ester hydrolyses catalyzed by human cholinesterases; Phys. Chem. B; 2005; 109; pp. 23070-23076.
Gao, et al; Computational design of a human butyrylcholinesterase mutant for accelerating cocaine hydrolysis based on the transition—state simulation; Angew. Chem. Int. Ed.; 2006; 45; pp. 653-657.
Gao, et al; Modeling evolution of hydrogen bonding and stablization of transition states in the process of cocaine hydrolysis catalyzed by human butyrylcholinesterase; Proteins; 2006; 62; pp. 99-110.
Hamza, et al.; Molecular dynamics simulation of cocaine binding with human butyrylcholinesterase and its mutants; J. Phys. Chem. B.; 2005; 109; pp. 4776-4782.
Pan, et al.; Computational redesign of human butyrylcholinesterase for anti-cocaine medication; G. Proc. Natl. Acad. Sci. USA; 2005; 102; pp. 16656-16661.
Zhan, et al.; Fundamental reaction mechanism for cocaine metabolism in human butyrylcholinesterase; J. Am. Chem. Soc.; 2003; 125; pp. 2462-2474.
Zhan, et al.; Catalytic Mechanism and energy barriers for butyrylcholinesterase—catalyzed hydrolysis of cocaine; Biophysical Journal; 2005; 89; pp. 3863-3872.
Xie, et al.; An improved cocaine hydrolase: the A328Y mutant of human butyrylcholinesterase is 4—fold more efficient; Moleculare Pharm; 1999; 55; pp. 83-91.
Cho Hoon
Tai Hsin-Hsiung
Zhan Chang-Guo
Decker Mandy Wilson
Saidha Tekchand
Stites & Harbison PLLC
University of Kentucky Research Foundation
Weyer Stephen
LandOfFree
High-activity mutants of butyrylcholinesterase for cocaine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with High-activity mutants of butyrylcholinesterase for cocaine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and High-activity mutants of butyrylcholinesterase for cocaine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-4200181