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


  • 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 and discovery through integrated computational-experimental studies. Drugs designed and discovered in Dr. Zhan’s lab are either small molecules (as inhibitors of enzymes or agonists/antagonists of receptor proteins or DNA-binding molecules etc.) or engineered proteins (mutants with significantly improved biological functions and/or increased circulation time in the body). In order to rationally design a drug, Dr. Zhan’s lab may perform whatever types of molecular modeling (including homology modeling and molecular docking), simulations (e.g. MD and Monte Carlo), calculations (e.g. QM, QM/MM, MM-PBSA, QM/MM-PBSA, FEP, and QM/MM-FEP etc.), statistical analysis (including QSAR and Artificial Neural Network), and molecular design (automated virtual screening and de novo design) that are necessary for a project. The computational 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 organizations) have been very productive, leading to exciting discovery of novel, promising therapeutics. One of the therapeutics has been licensed to a pharmaceutical company for clinical trials. 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 has been highlighted as news of magazines, such as IEEE magazine (, New Scientist (, and Chemical & Engineering News (  

Dr. Zhan has published more than 240 papers in peer-reviewed journals. He currently services as an Editorial Board member of multiple journals (including Theoretical Chemistry Accounts, Clinical Pharmacology, Journal of Addiction Research & Therapy, Reports in Theoretical Chemistry, and Medicinal Chemistry: Current Research). He currently serves or has served as member of American Association of Pharmaceutical Scientists (AAPS) Fellow Selection Committee, member of 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 NIH, NSF, DOE, and many other national and international foundations, and won 2005 Emerging Computational Technology Prize, American Chemical Society (ACS) Division of Computers in Chemistry (received during the Fall 2005 ACS meeting, Washington DC, August 28 to September 1, 2005; ACS web page for the prize:

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

  • Design and discover high-activity mutants of enzymes for enzyme therapy, particularly human butyrylcholinesterase (BChE) mutants as novel therapeutics for cocaine abuses;
  • Design and discover thermostable protein drugs, such as engineered cocaine esterase (CocE) for treatment of cocaine addiction and overdose;
  • Design and discover safe and efficient enzymes for detoxification of neurotoxic organophosphorus compounds and chemical warfare nerve agents;
  • 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 anti-inflammatory drugs;
  • Design and discover selective immunoproteasome inhibitors as anti-cancer drugs;
  • Design and discover selective PDK-1 inhibitors as anti-cancer drugs;
  • Design and discover novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 interaction (without blocking the APT-binding site) against pancreatic cancer;
  • Design chelators of neurotoxic metal ions for developing novel biomedical technology;
  • 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. 

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.
  • 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.; 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.
  • 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.

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