Chang-Guo Zhan

Contact Information

435 Bio Pharm Complex
789 South Limestone Street
Lexington, KY 40536-0596

phone: 859-323-3943
fax: 859-257-7585

Contact by email


  • Director
    Molecular Modeling and Biopharmaceutical Center
  • Director
    CPRI Chemoinformatics and Drug Design Core
  • Endowed College of Pharmacy Professor
    in Pharmaceutical Sciences
  • Professor
    Department of Pharmaceutical Sciences


  • Ph.D. in Molecular Physics
    Institute for Molecular Science (IMS), Japan
  • Ph.D. in Chemistry
    University of Notre Dame
  • Postdoctoral Research Scientist
    Columbia University (Department of Medicine)
  • Visiting Scientist
    Pacific Northwest National Laboratory


Chang-Guo Zhan, Ph.D.

Biographical Information and Research Interests
Chang-Guo Zhan received a Ph.D. in Chemistry (Physical Chemistry) from University of Notre Dame and a Ph.D. in Science (Molecular Physics) from Institute for Molecular Science (IMS), Japan (Graduate University of Advanced Studies). Dr. Chang-Guo Zhan performed his postdoctoral research as a Postdoctoral Research Scientist at Department of Medicine, Columbia University. After that, he served as Associate Research Scientist at Department of Medicine, Columbia University and a Visiting Scientist at Pacific Northwest National Laboratory at the same time. Dr. Zhan joined the UK College of Pharmacy faculty as Associate Professor in July 1st, 2003 and was promoted to Professor in July 1st, 2007. He was elected as Fellow of American Association of Pharmaceutical Scientists (AAPS) in 2010.

Dr. Zhan's main research interest is drug design, discovery, and development through integrated computational-experimental studies. Drugs designed and discovered in Dr. Zhan's lab are either small molecules or engineered proteins. Dr. Zhan's drug design and discovery efforts always start from rational design based on the detailed understanding of the molecular mechanisms. The rational design is followed by wet experimental tests (chemical synthesis, site-directed mutagenesis, protein expression, purification, in vitro activity assays, and in vivo tests etc.). These experiments are performed either in Dr. Zhan's lab or in a close collaboration with internal and/or external experimental laboratories. Dr. Zhan's unique "structure and mechanism based drug design and discovery" efforts through integrated computational-experimental studies (supported by NIH, NSF, and other funding agencies) have been very productive, leading to exciting discovery of novel, promising therapeutics. Two of the therapeutics designed in his lab are under clinical development; Phase II clinical trials have been completed, with positive outcomes. The members of Dr. Zhan's lab (including Graduate Students, Postdoctoral Fellows, Scientists, Visiting Scientists, and Visiting Professors) work in an interdisciplinary research environment. Some of Dr. Zhan's research work have been highlighted as news of magazines, such as Nature Chemical Biology, IEEE magazine, New Scientist, and ACS Chemical & Engineering News.

Dr. Zhan has published more than 300 articles in peer-reviewed journals, and received many national and international awards. More than 30 patents have been issued or filed for his inventions. Dr. Zhan currently services as an Editorial Board member of multiple journals. He has served on the American Association of Pharmaceutical Scientists (AAPS) Fellow Selection Committee, AAPS National Biotechnology Conference (NBC) programming committee, and Chair of Computational Drug Design Focus Group (CDDFG) of AAPS. He has served as a reviewer of grant proposals for the NIH, NSF, DOE, and many other national and international foundations

The current research activities in Dr. Zhan’s lab include:

  • Design and discover highly efficient drug-metabolizing enzymes for enzyme therapies, particularly human butyrylcholinesterase (BChE) mutants as novel therapeutics for cocaine addiction and overdose;
  • Design and discover thermally stable and long-acting protein therapeutics;
  • Design and discover safe and efficient enzymes for detoxification of neurotoxic organophosphorus compounds and chemical warfare nerve agents.
  • Design and discover novel drugs for obesity treatment;
  • Design and discover selective phosphodiesterase-2 (PDE2) inhibitors as novel memory enhancers and anxiolytic drugs;
  • Design and discover selective phosphodiesterase-5 (PDE5) inhibitors (that can reach CNS) as a novel treatment of severe Alzheimer's disease;
  • Design and discover mPGES-1 inhibitors as next generation of anti-inflammatory drugs;
  • Design and discover novel anti-cancer drugs (with novel targets);
  • Understand mechanisms of nicotinic acetylcholine receptors (nAChRs) interacting with agonists/antagonists for developing therapeutic treatment of nicotine addiction and neurodegenerative disorders;
  • Develop new computational methodologies/implementations and novel drug design approaches/strategies to support other drug design and discovery projects.
  • Other efforts including a number of collaborations with many other groups.

Selected Publications/Presentations

  • Zhan, C.-G.; Norberto de Souza, O.; Rittenhouse, R.; Ornstein, R. L. "Determination of two structural forms of catalytic bridging ligand in zinc-phosphotriesterase by molecular dynamics and quantum chemistry", J. Am. Chem. Soc. 1999, 121, 7279-7282.
  • Zhan, C.-G.; Landry, D. W.; Ornstein, R. L. “Theoretical studies of fundamental pathways for alkaline hydrolysis of carboxylic acid esters”, J. Am. Chem. Soc. 2000, 122, 1522-1530.
  • Zhan, C.-G.; Landry, D. W.; Ornstein, R. L. “Reaction pathways and energy barriers for alkaline hydrolysis of carboxylic acid esters in water studied by a hybrid supermolecule-polarizable continuum approach”, J. Am. Chem. Soc. 2000, 122, 2621-2627.
  • Zhan, C.-G.; Zheng, F. “First computational evidence for a critical bridging hydroxide ion in phosphodiesterase active site”, J. Am. Chem. Soc. 2001, 123, 2835-2838.
  • Koca, J.; Zhan, C.-G.; Rittenhouse, R.; Ornstein, R. L. “Mobility of the active site bound paraoxon and sarin in zinc-phosphotriesterase by molecular dynamics simulation and quantum chemical calculation”, J. Am. Chem. Soc. 2001, 123, 817-826.
  • Zhan, C.-G.; Zheng, F.; Dixon, D. A. “The electron affinities of Aln clusters and the multi-fold aromaticity of the square Al42- structure”, J. Am. Chem. Soc. 2002, 124, 14795-14803.
  • Zhan, C.-G.; Dixon, D. A.; Sabri, M.I.; Kim, M.-S.;  Spencer, P.S. “Chromophores in the chromogenic effects of neurotoxicants”, J. Am. Chem. Soc. 2002, 124, 2744-2752.
  • Zhan, C.-G.; Zheng, F.; Landry, D. W. “Fundamental reaction mechanism for cocaine metabolism in human butyrylcholinesterase”, J. Am. Chem. Soc. 2003, 125, 2462-2474.
  • Huang, X.; Zheng, F.; Crooks, P. A.; Dwoskin, L. P.; Zhan, C.-G. “Modeling multiple species of nicotine and deschloroepibatidine interacting with a4b2 nicotinic acetylcholine receptor: from microscopic binding to phenomenological binding affinity”, J. Am. Chem. Soc. 2005, 127, 14401-14414.
  • Pan, Y.; Gao, D.; Yang, W.; Cho, H.; Yang, G.; Tai, H.-H.; Zhan, C.-G. “Computational redesign of human butyrylcholinesterase for anti-cocaine medication”, Proc. Natl. Acad. Sci. USA 2005, 102, 16656-16661.
  • Gao, D.; Cho, H.; Yang, W.; Pan, Y.; Yang, G.-F.; Tai, H.-H.; Zhan, C.-G. “Computational design of a human butyrylcholinesterase mutant for accelerating cocaine hydrolysis based on the transition-state simulation”, Angew. Chem. Int. Ed. 2006, 45, 653-657.
  • Pan, Y.; Gao, D.; Yang, W.; Cho, H.; Zhan, C.-G. “Free energy perturbation (FEP) simulation on the transition-states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants”, J. Am. Chem. Soc. 2007, 129, 13537-13543.
  • Bargagna-Mohan1, P.; Hamza, A. Kim, Y.-E.; Ho, Y. K.; Mor-Vaknin, N.; Wendschlag, N.; Liu, J.; Evans, R. M.; Markovitz, D. M.; Zhan, C.-G.; Kim, K. B.; Mohan, R. "The Tumor Inhibitor and Anti-angiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin", Chemistry & Biology 2007, 14, 623-634 (Cover article).
  • Pan, Y.; Gao, D.; Zhan, C.-G. “Modeling the catalysis of anti-cocaine catalytic antibody: Competing reaction pathways and free energy barriers”, J. Am. Chem. Soc. 2008, 130, 5140-5149.
  • Huang, X.; Zheng, F.; Zhan, C.-G. “Modeling Differential Binding of a4b2 Nicotinic Acetylcholine Receptor with Agonists and Antagonists”, J. Am. Chem. Soc. 2008, 130, 16691-16696.
  • Zheng, F.; Yang, W.; Ko, M.-C.; Liu, J.; Cho, H.; Gao, D.; Tong, M.; Tai, H.-H.; Woods, J. H.; Zhan, C.-G. “Most efficient cocaine hydrolase designed by virtual screening of transition States”, J. Am. Chem. Soc. 2008, 130, 12148-12155.
  • Liu, J.; Hamza, A.; Zhan, C.-G. “Fundamental reaction mechanism and free energy profile for (-)-cocaine hydrolysis catalyzed by cocaine esterase”, J. Am. Chem. Soc. 2009, 131, 11964-11975.
  • Zhao, P.-L.; Wang, L.; Zhu, X.-L.; Huang, X.; Zhan, C.-G.; Wu, J.-W.; Yang, G.-F. “Subnanomolar inhibitor of cytochrome bc1 complex designed via optimizing interaction with conformationally flexible residues”, J. Am. Chem. Soc. 2010, 132, 185-194.
  • Li, D.; Huang, X.; Han, K.; Zhan, C.-G. “Catalytic mechanism of cytochrome P450 for 5΄-hydroxylation of nicotine: Fundamental reaction pathways and stereoselectivity”, J. Am. Chem. Soc. 2011, 133, 7416-7427.
  • Wei, D.; Lei, B.; Tang, M.; Zhan, C.-G. "Fundamental reaction pathway and free energy profile for inhibition of proteasome with a peptide", J. Am. Chem. Soc. 2012, 134, 10436-10450.
  • Zheng, 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.
  • Burikhanov, R.; Sviripa, V.M.; Hebbar, N.; Zhang, W.; Layton, W.J.; Hamza, A.; Zhan, C.-G.; Watt, D.S.; Liu, C.; Rangnekar, V.M. "Arylquin-1 targets vimentin to trigger Par-4 secretion for tumor cell apoptosis", Nature Chem. Biol. 2014, 10, 924-926. doi:10.1038/nchembio.1631.
  • Yuan, Y.; Huang, X.; Midde, N. M.; Quizon, P. M.; Sun, W. L.; Zhu, J.; Zhan, C.-G. "Molecular mechanism of HIV-1 Tat interacting with human dopamine transporter", ACS Chem. Neurosci. 2015, 6, 658-665; Research Highlight: ‚ÄúViral Mechanisms: Tat modulates DAT", Nature Chem. Biol. 2015, 11, 240.

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