Chang-Guo Zhan - Ph.D.

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 training 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 2003 and was promoted to Professor in July 2007.

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, and 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) have been very productive, leading to exciting discovery of novel, promising therapeutics. The members of Dr. Zhan's lab work in an interdisciplinary research environment. Some of Dr. Zhan's research work was highlighted as IEEE magazine news (http://csdl2.computer.org/comp/mags/cs/2006/04/c4006.pdf)

Dr. Zhan has published more than 180 papers in peer-reviewed journals and services as Advisory Editor of Theoretical Chemistry Accounts (a renowned international journal). He has been a member of NIH grant panel review committee in the "Drug Discovery and Development" study section (BCMB-L) and was the Winner of 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 award: http://membership.acs.org/C/COMP/set.html#Anchor-Fifth-47857.

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 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 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

• 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, revised.
• 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).
• 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.; 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.
• Huang, X.; Zheng, F.; Crooks, P. A.; Dwoskin, L. P.; Zhan, C.-G. "Modeling multiple species of nicotine and deschloroepibatidine interacting with 42 nicotinic acetylcholine receptor: from microscopic binding to phenomenological binding affinity", J. Am. Chem. Soc. 2005, 127, 14401-14414.
• 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.
• 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.; 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.
• 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. "First computational evidence for a critical bridging hydroxide ion in phosphodiesterase active site", J. Am. Chem. Soc. 2001, 123, 2835-2838./li>
• 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.; 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.; 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.

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