Dr. Fang Zheng is Co-PI on two major NIH grants (R01DA035552 and R01DA032910), and is responsible for the computational modeling and drug design related to cocaine in the collaborative projects.

Project title: Computational modeling and drug design related to cocaine

Summary of the project: Cocaine is a widely abused and hepatotoxic drug. Disastrous medical and social consequences of cocaine abuse have made it a high priority to develop a feasible anti-cocaine medication. Generally speaking, pharmacological treatment of drug abuse can be either pharmacodynamic or pharmacokinetic. The traditional pharmacodynamic approaches to cocaine addiction treatment include possible medications to target a specific subtype of transporters/receptors, which affect various neurotransmitter systems, such as dopaminergic, serotoninergic, noradrenergic, cholinergic, glutamatergic, GABAergic, and opioidergic pathways, and modulate neurological processes. However, despite of decades of effort, pharmacodynamic treatment of cocaine abuse has been proven very elusive. There is still no FDA-approved medication specific for cocaine addiction or overdose. In addition, cocaine abuse is also closely related to HIV infection and interacts with other drugs. We will first computationally study how cocaine and other related drugs/compounds interact with various proteins and then design possible therapeutic candidates for treatment of cocaine abuse and related problems.

Software:

Amber, Charmm, Gaussian, AutoDock, AutoDock Vino, Tripos?, and MatLab etc.

Research Personnel:

Zheng, Dr. Fang - Co PI
Zhan, Prof. Chang-Guo - Co PI
Zhang, Yuxin - Visiting Scholar
Zhu, Yanyan
Chen, Yao - Visiting Scholar

Funding:

NIH grants (UH2/UH3 DA041115, R01 DA035552, and R01 DA032910)

Publications:

2016

Chen, X.; Zheng, X.; Zhan, M.; Zhou, Z.-Y.; Zhan, C.-G.; Zheng, F. “Metabolic enzymes of cocaine metabolite benzoylecgonine”, ACS Chem. Biol. 2016, 11, 2186-2194.
Zhang, Y.; Huang, X.; Han, K.; Zheng, F.; Zhan, C.-G. “Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations”, Chem. Biol. Interact. 2016, May 6 Epub ahead of print.
Zheng, X.; Zhang, T.; Zheng, F.; Zhan, C.-G. “Potential anti-obesity effects of a long-acting cocaine hydrolase”, Chem. Biol. Interact. 2016, May 6 Epub ahead of print.
Chen, X.; Zheng, X.; Zhan, C.-G.; Zheng, F. “Effects of a cocaine hydrolase engineered from human butyrylcholinesterase on metabolic profile of cocaine in rats”, Chem. Biol. Interact. 2016, May 3 Epub ahead of print.
Zheng, F.; Zhan, C.-G. “Reply to Curry and Coombs: Benzoic acid is formed predominantly from the benzoyl ester hydrolysis in the presence of cocaine hydrolase”, Proc. Natl. Acad. Sci. USA 2016, 113(15), E2102-2103.
Yao, J.; Yuan, Y.; Zheng, F.; Zhan, C.-G. “Unexpected reaction pathway for butyrylcholinesterase-catalyzed inactivation of ‘hunger hormone’ ghrelin”, Sci. Rep. 2016, 6, 22322; doi: 10.1038/srep22322.
Zheng, F.; Zhan, C.-G. “Actions of Butyrylcholinesterase Against Cocaine”, accepted for publication as a chapter of book entitled The Neuroscience of Cocaine: Mechanisms and Treatment, edited by Victor R. Preedy, to be published by Academic Press, an Imprint of Elsevier in 2016.
Zheng, F.; Zhan, C.-G. “Cocaine Hydrolases Designed from Butyrylcholinesterase” (invited review as a chapter), In Biologics to Treat Substance Use Disorders: Vaccines, Monoclonal Antibodies, and Enzymes; Ivan D. Montoya, Ed.; Springer, Heidelberg, Germany, 2016; p 187-225.
Yao, Y.; Liu, J.; Zheng, F.; Zhan, C.-G. “Reaction pathway for cocaine hydrolase-catalyzed hydrolysis of (+)-cocaine”, Theo. Chem. Acc. 2016, 135, 15.
Chen, X.; Xue, L.; Hou, S.; Jin, Z.; Zhang, T.; Zheng, F.; Zhan, C.-G. “Long-acting cocaine hydrolase for addiction therapy”, Proc. Natl. Acad. Sci. USA 2016, 113(2), 422-427.

2015

11. Chen, X.; Huang, X.; Geng, L.; Xue, L.; Hou, S.; Zheng, X.; Brimijoin, S.; Zheng, F.; Zhan, C.-G. “Kinetic characterization of a cocaine hydrolase engineered from mouse butyrylcholinesterase”, Biochem. J. 2015, 466, 243-251.

2014

Zhan, M.; Hou, S.; Zhan, C.-G.*; Zheng, F.* “Kinetic characterization of high-activity mutants of human butyrylcholinesterase for the cocaine metabolite norcocaine”, Biochem J. 2014, 457(1):197-206.
Fang, L.; Zheng, F.; Zhan, C.-G. “A model of glycosylated human butyrylcholinesterase”, Mol. BioSyst. 2014, 10, 348-354.
1Zheng, F.; Xue, L.; Hou, S.; Liu, J.; Zhan, M.; Yang, W.; Zhan, C.-G. “A highly efficient cocaine detoxifying enzyme obtained by computational design”, Nature Commun. 2014, 5, 3457 (DOI: 10.1388/ncomms4457).
Fang, L.; Chow, K. M.; Hou, S.; Xue, L.; Rodgers, D. W.; Zheng, F.; Zhan, C.-G. “Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification”, ACS Chem. Biol. 2014, 9, 1764-1772.
Hou, S.; Zhan, M.; Zheng, X.; Zhan, C.-G.; Zheng, F. “Kinetic characterization of human butyrylcholinesterase mutants for hydrolysis of cocaethylene”, Biochem. J. 2014, 460, 447-457.
Fang, L.; Hou, S.; Xue, L.; Zheng, F.; Zhan, C.-G. “Amino-acid mutations to extend the biological half-life of a therapeutically valuable mutant of human butyrylcholinesterase”, Chem. Biol. Interact. 2014, 214, 18-25.
Zheng, F.; Zhan, M.; Huang, X.; AbdulHameed, M.; Zhan, C.-G. “Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches”, Bioorg. Med. Chem. 2014, 22, 538-549.

2013

Zheng, F.*; Zhan, M.; Huang, X.; Abdul Hameed, M. D.; Zhan, C.-G.* “Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches”, Bioorg Med Chem. 2013 Nov 8. pii: S0968-0896(13)00927-9. doi: 10.1016/j.bmc.2013.10.053. Epub ahead of print Fang L, Zheng F, Zhan CG. “A model of glycosylated human butyrylcholinesterase”, Mol Biosyst. 2013 Dec 11. Epub ahead of print
Hou, S.; Xue, L.; Yang, W.; Fang, L.; Zheng, F.; Zhan, C.-G. “Substrate selectivity of high-activity mutants of human butyrylcholinesterase”, Org Biomol Chem. 2013, 11(43):7477-85.
Huang, X.; Zheng, F.; Zhan, C.-G. “Binding structures and energies of the human neonatal Fc receptor with human Fc and its mutants by molecular modeling and dynamics simulations”, Mol Biosyst. 2013, 9(12):3047-58.
Xue, L.; Hou, S.; Tong, M.; Fang, L.; Chen, X.; Jin, Z.; Tai, H. H.; Zheng, F.; Zhan, C.-G.“Preparation and in vivo characterization of a cocaine hydrolase engineered from human butyrylcholinesterase for metabolizing cocaine”, Biochem J. 453(3), 447-54 (2013).
Zheng, F. ; Zhan, C.-G., “Computational Modeling of Solvent Effects on Protein-Ligand Interactions Using Fully Polarizable Continuum Model and Rational Drug Design”, Commun. Comput. Phys. 13, 31-60 (2013).
Ring, J. R.†; Zheng, F.†; Haubner, A. J.; Littleton, J. M.; Crooks, P. A., “Improving the inhibitory activity of arylidenaminoguanidine compounds at the N-methyl-Daspartate receptor complex from a recursive computational-experimental structure-activity relationship study”, Bioorganic & Medicinal Chemistry 21(7), 1764-1774 (2013).
Xue L.; Hou S.; Yang W.; Fang L.; Zheng F.; Zhan C.-G., “Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (-)-cocaine”, Chem. Biol. Interact. 203(1), 57-62 (2013).

2012

Huang X.; Zhao X.; Zheng F.; Zhan C.-G., “Cocaine esterase-cocaine binding process and the free energy profiles by molecular dynamics and potential of mean force simulations”, J. Phys. Chem. B 116(10), 3361-3368 (2012).
Zheng, F.; Zhan, C.-G., “Modeling of Pharmacokinetics of Cocaine in Human Reveals the Feasibility for Development of Enzyme Therapies for Drugs of Abuse”, PLoS Computational Biology 8(7), e1002610 (2012).
Zheng, F.; Zhan, C.-G., “Are Pharmacokinetic Approaches Feasible for Treatment of Cocaine Addiction and Overdose?”, Future Medicinal Chemistry (editorial) 4(2), 125-128 (2012).

2011

Crooks, P. A.; Zheng, G.; Vartak, A. P.; Culver, J. P.; Zheng, F.; Horton, D. B.; Dwoskin, L. P., “Design, Synthesis and Interaction at the Vesicular Monoamine Transporter-2 of Lobeline Analogs. Potential Pharmacotherapies for the Treatment of Psychostimulant Abuse”, Current Topics in Medicinal Chemistry 11, 1103-1127 (2011).
Xue, L.; Ko, M.-C.; Tong, M.; Yang, W.; Hou, S.; Fang, L.; Liu, J.; Zheng, F.; Woods, J. H.; Tai, H.-H; Zhan, C.-G., “Design, Preparation, and Characterization of High-Activity Mutants of Human Butyrylcholinesterase Specific for Detoxification of Cocaine”, Molecular Pharmacology 79(2), 290-297 (2011).
Zheng, F.; Zhan, C.-G., “Enzyme-Therapy Approaches for the Treatment of Drug Overdose and Addiction”, Future Medicinal Chemistry 3(1), 9-13 (2011).
Huang, X.; Zheng, F.; Zhan, C.-G., “Human Butyrylcholinesterase-Cocaine Binding Pathway and Free Energy Profiles by Molecular Dynamics and Potential of Mean Force Simulations”, Journal of Physical Chemistry B 115(38), 11254-11260 (2011)

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