High-activity mutants of butyrylcholinesterase for cocaine...

Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases

Reexamination Certificate

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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:
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patent: 2003/0153062 (2003-08-01), Watkins et al.
patent: 2004/0120939 (2004-06-01), Watkins et al.
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