This project focuses on the rational redesign of human butyrylcholinesterase (BChE) in order to accelerate cocaine metabolism in man. Enhancing cocaine metabolism by administration of BChE has been recognized as a possible treatment strategy for cocaine overdose and addiction. However, the catalytic activity of this plasma enzyme is three orders-of-magnitude lower against the naturally occurring (-)-cocaine than that against the relatively biologically inactive (+)-cocaine isomer. (+)-cocaine can be cleared from plasma in seconds prior to partitioning into the central nervous system. The long-term goal of this project is to guide the construction of a BChE mutant using site-directed mutagenesis by our collaborators so that the mutant can be used as an exogenous enzyme in human body with a catalytic activity for (-)-cocaine comparable to that of wild-type BChE for (+)-cocaine. For this purpose, state-of-the-art computational techniques will be used to uncover the mechanistic difference of the enzymatic reaction between (-)-cocaine and (+)-cocaine and to establish a rational basis for theoretical design of BChE mutants with an improved activity for (-)-cocaine.
The specific aims of the investigation involved in the present proposal include: 1. To determine structures and dynamics of the BChE binding with (-)-cocaine and (+)-cocaine, including the non-prereactive and prereactive BChE-substrate complexes. 2. To uncover fundamental reaction pathways for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine at the benzoyl ester by performing reaction coordinate calculations on properly chosen model systems; 3. To investigate dynamics and changes of BChE binding with (-)-cocaine and (+)-cocaine during the enzymatic hydrolysis by carrying out MD simulations on the enzyme-reactant, transition state, intermediate and product complexes; 4. To evaluate free energy profiles and kinetics of the enzymatic hydrolysis by performing combined quantum mechanical and free energy perturbation calculations (QM-FE); 5. To design BChE mutants expected to have higher activity for (-)-cocaine based on the binding information obtained from Specific Aim 2 and the energetic information from Specific Aim 3. ? ?
|Yuan, Yaxia; Zheng, Fang; Zhan, Chang-Guo (2018) Improved Prediction of Blood-Brain Barrier Permeability Through Machine Learning with Combined Use of Molecular Property-Based Descriptors and Fingerprints. AAPS J 20:54|
|Zhang, Ting; Zheng, Xirong; Kim, Kyungbo et al. (2018) Blocking drug activation as a therapeutic strategy to attenuate acute toxicity and physiological effects of heroin. Sci Rep 8:16762|
|Chen, Xiabin; Deng, Jing; Cui, Wenpeng et al. (2018) Development of Fc-Fused Cocaine Hydrolase for Cocaine Addiction Treatment: Catalytic and Pharmacokinetic Properties. AAPS J 20:53|
|Kim, Kyungbo; Yao, Jianzhuang; Jin, Zhenyu et al. (2018) Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine. Chem Biol Interact 293:107-114|
|Kim, Kyungbo; Zheng, Fang; Zhan, Chang-Guo (2018) Oligomerization and Catalytic Parameters of Human UDP-Glucuronosyltransferase 1A10: Expression and Characterization of the Recombinant Protein. Drug Metab Dispos 46:1446-1452|
|Zheng, Xirong; Zhou, Ziyuan; Zhang, Ting et al. (2017) Effectiveness of a Cocaine Hydrolase for Cocaine Toxicity Treatment in Male and Female Rats. AAPS J 20:3|
|Chen, Xiabin; Zheng, Xirong; Ding, Kai et al. (2017) A quantitative LC-MS/MS method for simultaneous determination of cocaine and its metabolites in whole blood. J Pharm Biomed Anal 134:243-251|
|Zhang, Ting; Zheng, Xirong; Zhou, Ziyuan et al. (2017) Clinical Potential of an Enzyme-based Novel Therapy for Cocaine Overdose. Sci Rep 7:15303|
|Jin, Yafei; Huang, Xiaoqin; Papke, Roger L et al. (2017) Design, synthesis, and biological activity of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors. Bioorg Med Chem Lett 27:4350-4353|
|Yuan, Yaxia; Huang, Xiaoqin; Zhu, Jun et al. (2016) Computational modeling of human dopamine transporter structures, mechanism and its interaction with HIV-1 transactivator of transcription. Future Med Chem 8:2077-2089|
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