Zhan, Chang-Guo

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Jun 09, 2024
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Research Projects in Dr. Chang-Guo Zhan’s Lab

Updated November 20, 2013
A. Project Description
Current research in Dr. Zhan’s lab is rational drug design, discovery and development through integrated computational-experimental studies. All of the projects in our lab start from molecular modeling and rational design based on high-performance supercomputing. Drug candidates 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 own lab or in a close collaboration with internal and/or external experimental laboratories. Dr. Zhan’s unique “structure-and­mechanism-based drug design and discovery” efforts through integrated computational-experimental studies have been very productive, leading to exciting discovery of novel, promising therapeutics. Two of the drug candidates designed in his lab are currently in Phase II clinical trials in humans.

Lab Software:

Gaussian, Amber, OpenEye, NAMD, AutoDock, Vina, MVD (for which we need to have license), Modeler, Sybyl, Discovery Studios, GPUs, MaestroDesmond, Glide (for which we need to have license), Rosetta, ZDock, MatLab, ADMET Predictor, CAVITY(in-house software), LigBuilder (in­house software), Gromacs, Modified Gaussian-Amber programs (in-house software), and LexDock (in­house software), CHARMM.

From supercomputing point of views, all of the research activities in Dr. Zhan’s lab belong to four major projects (each project may involve one of more research grants).

Development of novel computational methods for studying molecular structures, properties, and reaction mechanisms in solution.

This project aims to develop new computational methods and the corresponding computer software that can be used to reliably study molecular structures, properties and chemical/biochemical reaction mechanisms and to design new drug candidates. Examples of our new computational methods under development: (1) a generalized implementation of first-principles electronic structure method accounting for solvent effects, (2) a new QM/MM implementation, and (3) various new methods for computational drug design.

Software:

Gaussian, Amber, LexDock, and modified Gaussian-Amber programs, CHARMM

Research Participants:

Dr. Fang Zheng
Dr. Junjun Liu
Dr. Xi Chen
Min Yao
Dr. Jianzhuang Yao
Dr. Zhe Li
Dr. Meiju Wei
Dr. Misha Webber

Priyanka Suryadevara, Post Doc, Added 04/01/2021

Bhanuchandar Nellore, Post Doc, Added on LCC, 01/14/2022

James Ogidi, Graduate, Added on LCC, 08/10/2023 

Computational studies on biomolecular mechanisms.

In this project, a variety of computational methods (including our own methods developed in Project #1) are employed to study a variety of biomolecular interactions and transformations, such as protein-protein interactions, protein-ligand interactions, and the detailed catalytic mechanisms for enzymatic reactions. The detailed computational studies in this project provide a solid base for further computational drug design efforts in Projects #3 and #4 described below.

Software:

Gaussian, Amber, NAMD, AutoDock,
Modeler, Sybyl, Discovery Studios, ZDock, Gromacs, Rosetta, Modified Gaussian-Amber, LexDoc, CHARMM

Research Participants:

Dr. Yaxia Yua
Dr. Yanyan Zhu
Yuxin Zhang
Dr. Junjun Liu
Dr. Xi Chen
Min Yao
Dr. Donghui Wei
Dr. Yan Qiao
Max Zhan
Dr. Jianzhuang
Dr. Misha Webber

Computational design of novel protein drugs.

In this project, a variety of computational methods (including our own methods developed in Project #1) are employed to design new protein entities that could be used as therapeutic agents. The therapeutic agents to be designed include cocaine-metabolizing enzymes that can serve as exogenous enzymes to accelerate cocaine metabolism and detoxification.

Software:

Gaussian, Amber, ZDock, Gromacs, MatLab,
Modified Gaussian-Amber, CHARMM

Research Participants:

Dr. Fang Zheng
Dr. Yaxia Yuan
Dr. Jianzhuang Yao
Dr. Yanyan Zhu
Yuxin Zhang
Dr. Junjun Liu
Dr. Xi Chen
Min Yao
Dr. Donghui Wei
Dr. Liu Xue
Yan Qiao
Dr. Xiaoqin Huang
Dr. Lei Fang
Max Zhan
Chunhui Zhang, Visiting Scholar/Staff
Dr. Misha Webber


Computational design of novel small-molecule drugs.

In this project, a variety of computational methods (including our own methods developed in Project #1) are employed to design small-molecule compounds (such as inhibitors of enzymes or agonists/antagonists of receptor proteins or DNA-binding
molecules etc.) that could be used as novel therapeutic agents (such as anti-cancer drugs and nextgeneration anti-inflammatory drugs).

Software:

Gaussian, Amber, OpenEye, NAMD,
AutoDock, Vina, MVD, Modeler, Sybyl, Discovery Studios, Maestro/Desmond, Glide, ADMET Predictor, CAVITY, and LigBuilder

Research Participants:

Dr. Fang Zheng
Dr. Yaxia Yuan
Dr. Yanyan Zhu
Yuxin Zhang
Ziyuan Zhou
Shuo Zhou
Max Zhan
Dr. Junjun Liu
Dr. Aibin Wu
Dr. Xi Chen
Kuo Hao Lee, Scientist I

Alexander H Williams, Grad Student 03/29/2018 

Computational Methods To Be Used

First-principle electronic structure theory (QM methods); QM/MM methods; Homology modeling; Molecular dynamics (MD) simulations using MM force field; MD simulations using QM/MM force field; Free energy perturbation; Molecular docking; Protein-protein docking; Molecular shape fitting; Ligand-based virtual screening; Structure-based virtual screening; De novo drug design; ADMET prediction; Kinetic modeling.



UK collaborators:

Dr. Fang Zheng
Dr. Yaxia Yuan
Dr. Jianzhuang Yao
Dr. Yanyan Zhu
Yuxin Zhang
Ziyuan Zhou
Shuo Zhou
Max Zhan

Non-UK collaborators:

Dr. Junjun Liu
Dr. Xi Chen
Dr. Donghui Wei
Dr. Yuan Yao
Dr. Xinyun Zhao
Dr. Xiaoqin Huang
Yan Qiao
Dr. Liu Xue
Dr. Lei Fang
Min Yao



Grants

Zhan, Chang-Guo 5R01DA013930-08 Redesign of Butyrylcholinesterase for Cocaine Metabolism $2,022,439 National Institute on Drug Abuse 8/20/2003 5/31/2014
Zhan, Chang-Guo 5R01DA025100-05 High-Activity Mutants of Cocaine Esterase for Treatment of Drug Addiction $2,538,075 National Institute on Drug Abuse 8/15/2008 6/30/201
Zhan, Chang-Guo CHE-1111761 Development of First-Pinciples Electronic Structure Approach for Studying Molecular Structures, Properties, and Reaction Mechanisms in Solution $291,607 National Science Foundation 9/1/2011 8/31/2015
Zhan, Chang-Guo 5R01DA032910-02 Development of Cocaine-Metabolizing Enzyme for Drug Overdose Treatment $1,177,985 National Institute on Drug Abuse 3/1/2012 2/28/2015
Zhan, Chang-Guo 39672 Development_of_M5_Selective_Muscarinic_Antagonists $53,210 University of Arkansas 6/1/2012 5/31/2014
Zhan, Chang-Guo 1R01DA035552-01 Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment $1,176,703 National Institute on Drug Abuse 4/1/2013 2/29/2016
Zhan, Chang-Guo 14-2449 PO# 81368 Impact of HIV-1 Tat Protein on Cocaine-Dopamine Transporter Interaction $309,813 University of South Carolina 7/31/2013 3/31/2018
Zhan, Chang-Guo 3R01DA032910-02S1 Summer Research with NIDA 2013: Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment National Institute on Drug Abuse 3/1/2012 - /28/2015 SCOPE
Zhan, Chang-Guo 1R01DA035552-02 Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment National Institute on Drug Abuse 4/1/2013 - 2/29/2016 $2,274,407
Zhan, Chang-Guo 5R01DA032910-03 Development of Cocaine-Metabolizing Enzyme for Drug Overdose Treatment National Institute on Drug Abuse 3/1/2012 - 2/28/2015 $1,824,823

Funding:

Currently Active Federal Grants:
1.
Active: “Development of first-principles electronic structure approach for studying molecular structures, properties, and reaction mechanisms in solution”, NSF CHE-1111761, $291,607 for 9/1/2011 – 8/31/2015. The goal is to develop novel computational methodology of solvation theory and employ the developed methodology to study important biological problems. My role: PI.

2.
Active: “Long-lasting Cocaine-metabolizing Enzyme for Cocaine Addiction Treatment”, NIH R01 DA035552, $3,379,885 for 4/1/2013 – 2/29/2016. This investigation aims to develop a novel formulation of our previously invented enzyme therapy for drug addiction treatment. My role: PI.

3.
Active: “Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment”, NIH R01 DA032910, $1,842,800 for 3/1/2012 – 2/28/2015. This investigation aims to develop a novel therapeutic treatment of cocaine overdose by using a highly efficient cocaine hydrolase which we have discovered in another NIH-funded investigation. My role: PI.

4.
Active: “High-Activity Mutants of Cocaine Esterase for Treatment of Drug Addiction”, NIH R01 DA025100, $2,550,667 for 8/15/08 – 6/30/15. The goal is to understand the detailed catalytic mechanism for cocaine hydrolysis catalyzed by cocaine esterase and design its high-active mutants for treatment of cocaine addiction. This is a multiple-PI project involving three universities and five research laboratories. My role: Contact PI. The other PIs are Dr. James H. Woods at University of Michigan and Dr. Donald W. Landry at Columbia University.


5.
Active: “Impact of HIV-1 Tat Protein on Cocaine-Dopamine Transporter Interaction”, NIH R01 DA035714 for $1,842,948 for 7/1/2013 – 6/30/2018 (PI: Zhu at USC). The goal is to understand the molecular mechanism for effects of HIV-1 Tat protein on cocaine-dopamine transporter interaction. My role: Co-I responsible for computational modeling and design/predictions (subaward budget to me: $814,407).

6.
Active: “Novel Resveratrol Analogs and Colorectal Cancer Treatment”, NIH R01 CA172379, $1,559,277 for 8/6/2013 – 5/31/2018 (PI: Liu). This study is for discovery of a novel anti-cancer drug. My role: Co-I responsible for oversight of computational modeling and design.

7.
Active: “Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment – Supplemental Funds for NIDA Undergraduate and High School Student Summer Research with NIDA”, NIH R01 DA032910-02S1, $6,432 for 6/1/2013 – 2/28/2015. This investigation aims to develop a novel therapeutic treatment of cocaine overdose by using a highly efficient cocaine hydrolase which we have discovered in another NIH-funded investigation. My role: PI.

8.
Active: “A Device Containing Immobilized Chelator to Remove Aluminum from TPN Solutions”, NIH R41/42 HD055009, $860,208 (the total costs including Kentucky State matching funds) for 3/01/2008 – 5/31/2015 (PI: Robert A. Yokel). The goal is to design, discover, and develop a device to remove aluminum from TPN solutions. My role: Co-Investigator responsible for computational design of new chelators.

9.
Active: “A Device Containing Immobilized Chelator to Remove Aluminum from TPN Solutions”, Kentucky Commercialization Funds (for matching NIH award R41/42 HD055009), $713,542 (the total costs including Kentucky State matching funds) for 3/01/2008 – 5/31/2015 (PI: Robert A. Yokel). The goal is to design, discover, and develop a device to remove aluminum from TPN solutions. My role: Co-Investigator responsible for computational design of new chelators.

10.
Active: “Training in Drug Abuse Related Research” program (Program Director: Louis B. Hersh/Linda Dwoskin), NIH T32 DA016176, ~$1.3M for 7/1/2014 – 6/30/2019 (renewed on 7/1/2014). This is a training program grant for jointly training graduate students and postdoctoral fellows in drug abuse related research. My role: A member of the training faculty.


Publications:

Recent Publications Involving Supercomputing Studies at UK during the Last Five Years

2014


1. 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-1targets vimentin to trigger Par-4 secretion for tumor cell apoptosis”, Nature Chem. Biol. 2014, in press.
2. 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 Epub ahead of print: June 11, 2014.
3. 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.
4. Kasam, V.; Lee, N.-R.; Kim, K.-B.; Zhan, C.-G. “Selective immunoproteasome inhibitors with non-peptide scaffolds identified from structure-based virtual screening”, Bioorg. Med. Chem. Lett. 2014, 24, 3614-3617.
5. Sviripa, V.M.; Zhang, W.; Kril, L.M.; Liu, A.X.; Yuan, Y.; Zhan, C.-G.; Liu, C.; Watt, D.S. “Halogenated diarylacetylenes repress c-myc expression in cancer cells”, Bioorg. Med. Chem. Lett. 2014, 24, 3638-3640.
6. 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.
7. Hamza, A.; Wagner, J.M.; Evans, T.J.; Frasinyuk, M.S.; Kwiatkowski, S.; Zhan, C.-G.; Watt, D.S.; Korotkov, K.V. “Novel mycosin protease MycP1 inhibitors identified by virtual screening and 4D fingerprints”, J. Chem. Inf. Modeling 2014, 54, 1166-1173.
8. Hao, G.-F.; Zhan, C.-G.; Yang, G.-F. “Mechanistic insights into the substrate recognition of PPO: toward the rational design of effective inhibitors” (Editorial), Future Med. Chem. 2014, 6, 597-599.
9. Lu, H.; Huang, X.; AbdulHameed, M. D.; Zhan, C.-G. “Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations”, Bioorg. Med. Chem. 2014, 22, 2149-2156.
10. Wang, Z.-X.; Sun, J.; Howell, C. E.; Zhou, Q.-Y.; Zhou, Z.-W.; He, Z.-X.; Yang, T.; Liang, J.; Yang, Y.; Chow, K.; Zhan, C.-G.; Chen, X.; Duan, W.; Kanwar, J. R.; Liu, J.-P.; Zhou, S.-F. “Prediction of the likelihood of drug interactions with kinase inhibitors based on in vitro and computational studies”, Comb. Chem. High Throughput Screen. 2014, in press.
11. Qiao, Y.; Han, K.; Zhan, C.-G. “Reaction pathways and free energy profiles for 6-monoacetylmorphine hydrolysis in acetylcholinesterase and butyrylcholinesterase”, Org. Biomol. Chem. 2014, 12(14), 2214-2227 (Cover Article).
12. 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.
13. Shaaban, K.; Fang, L.; Ponomareva, L.; Zhang, Y.; Copley, G.; Hower, J.; Zhan, C.-G.; Kharel, M.; Thorson, J. “Ruthmycin, a novel tetracyclic polyketide from Streptomyces sp. RM-4-15”, Org. Lett. 2014, 16, 456-459.
14. 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.
15. Zhan, M.; Hou, S.; Zhan, C.-G.; Zheng, F. “Kinetic characterization of high-activity mutants of human butyrylcholinesterase for cocaine metabolite norcocaine”, Biochem. J. 2014, 457, 197-206.

2013

1.
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”, Mol. BioSyst. 2013, submitted.

2.
Lu, H.; Huang, X.; AbdulHameed, M. D.; Zhan, C.-G. “Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations”, Bioorg. Med. Chem. 2013, submitted (currently in revision).

3.
Zheng, F.; Xue, L.; Hou, S.; Yang, W.; Liu, J.; Zhan, C.-G. “An extraordinarily efficient enzyme
specific for cocaine detoxification from computational design”, Nature Communications 2013,
submitted (currently in revision).

4.
Fang, L.; Zheng, F.; Zhan, C.-G. “Model of glycosylated human butyrylcholinesterase”, Mol.
BioSyst. 2013, in press.

5.
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. 2013, in press.

6.
Zhan, M.; Hou, S.; Zhan, C.-G.; Zheng, F. “Kinetic characterization of high-activity mutants of human butyrylcholinesterase for cocaine metabolite norcocaine”, Biochem. J. 2013, 457, 197-206.

7.
Qiao, Y.; Han, K.; Zhan, C.-G. “Fundamental reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of heroin”, Biochemistry 2013, 52, 6467-6479.

8.
Wei, D.; Fang, L.; Tang, M.; Zhan, C.-G. “Fundamental reaction pathway for peptide metabolism by proteasome: Insights from first-principles quantum mechanical/molecular mechanical free energy calculations”, J. Phys. Chem. B 2013, 117, 13418-13434.

9.
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, 7477-7485.

10.
Yao, M.; Tu, W.; Chen, X.; Zhan, C.-G. “Reaction pathways and free energy profiles for spontaneous hydrolysis of urea and tetramethylurea: Unexpected substituent effects”, Org. Biomol. Chem. 2013, 11, 7595-7605.

11.
Huang, X.; Zheng, F.; Zhan, C.-G. “Binding structures and energies of human neonatal Fc receptor with human Fc and its mutants by molecular modeling and dynamics simulations”, Mol. BioSyst. 2013, 9, 3047-3058.

12.
Midde, N.M.; Huang, X.; Gomez, A.M.; Booze, R.M.; Zhan, C.-G.; Zhu, J. “Mutation of tyrosine 470 of human dopamine transporter is critical for HIV-1 Tat-induced inhibition of dopamine transport and transporter conformational transitions”, J. Neuroimmune Pharmacol. 2013, 8(4), 975­-987.

13.
Wei, D.; Huang, X.; Liu, J.; Tang, M.; Zhan, C.-G. “Reaction pathway and free energy profile for papain-catalyzed hydrolysis of N-acetyl-Phe-Gly 4-nitroanilide”, Biochemistry 2013, 52, 5145­5154.

14.
Hao, G.-F.; Yang, G.-F.; Zhan, C.-G. “Computational Gibberellin-binding channel discovery unraveling the unexpected perception mechanism of hormone signal by Gibberellin receptor”, J. Comput. Chem. 2013, 34, 2055-2064 (Cover Article).

15.
Wei, N.-N.; Hamza, A.; Hao, C.; Xiu, Z.; Zhan, C.-G. “Microscopic modes and free energies for topoisomerase I-DNA covalent complex binding with non-campothecin inhibitors by molecular docking and dynamics simulations”, Theor. Chem. Acc. 2013, 132, 1379.

16.
Hao, G.-F.; Tan, Y.; Wang, Z.-F.; Yang, S.-G.; Zhan, C.-G.; Xi, Z.; Yang, G.-F. “Computational and experimental insights into the mechanism of substrate perception and feedback inhibition of protoporphyrinogen oxidase”, PLoS One 2013, 8, e69198.

17.
Zheng, G.; Smith, A.; Huang, X.; Subramanian, K.; Siripurapu, K.; Deaciuc, A.; Zhan, C.-G.; Dwoskin, L. “Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists”, J. Med. Chem. 2013, 56, 1693-1703.

18.
Zhou, M.; Hamza, A.; Zhan, C.-G.; Thorson, J.S. “Assessing the regioselectivity of OleD-catalyzed glycosylation with a diverse set of acceptors”, J. Nat. Prod. 2013, 76, 279-286.

19.
Zhang, W.; Sviripa, V.; Chen, X.; Shi, J.; Yu, T.; Hamza, A.; Ward, N.D.; Kril, L.M.; Vander Kooi, C.W.; Zhan, C.-G.; Evers, B.M.; Watt, D.S.; Liu, C. “Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A”, ACS Chem Biol. 2013, 8, 796-803.

20.
Li, D.; Huang, X.; Lin, J.; Zhan, C.-G. “Catalytic mechanism of cytochrome P450 for N­methylhydroxylation of nicotine: Reaction pathways and regioselectivity of the enzymatic nicotine oxidation”, Dalton Trans. 2013, 42, 3812-3820.

21.
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. 2013, 13, 31-60.

22.
Wei, N.N.; Hamza, A.; Hao, C.; Johnson-Scalise, T.; Xiu, Z.; Naftolin, F.; Zhan, C.-G. “Protein flexibility and conformational states of Leishmania antigen eIF-4A: Identification of a novel plausible protein adjuvant using comparative genomics and molecular modeling”, J. Biomol. Struct. Dyn. 2013, 31(8), 841-853.

23.
Hamza, A.; Wei, N.N.; Hao, C.; Xiu, Z.; Zhan, C.-G. “A novel and efficient ligand-based virtual screening approach using the HWZ scoring function and an enhanced shape-density model”, J. Biomol. Struct. Dyn. 2013, 31(11), 1236-1250.

24.
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. 2013, 203, 57-62.

2012

1.
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.

2.
Yao, Y.; Liu, J.; Zhan, C.-G. “Why does the G117H mutation considerably improve the activity of human butyrylcholinesterase against sarin? Insights from quantum mechanical/molecular mechanical free energy calculations”, Biochemistry 2012, 51, 8980-8992.

3.
Zhou, M.; Hou, Y.; Hamza, A.; Pain, C.; Zhan, C.-G.; Bugni, T.S.; Thorson, J.S. “Probing the regiospecificity of enzyme-catalyzed steroid glycosylation”, Org. Lett. 2012, 14, 5424-5427.

4.
Sharma, L. K.; Lee, N.-R.; Jang, E. R.; Lei, B.; Zhan, C.-G.; Lee, W.; Kim, K.-B. “Near-infrared activity-based fluorescent probe for LMP7: A chemical proteomics tool for immunoproteasome in living cells”, ChemBioChem. 2012, 13, 1899-1903.

5.
Hao, G.; Yang, G.; Zhan, C.-G. “Computational prediction of drug resistance and anti-resistance drug design”, Drug Discovery Today, 2012, 17, 1121-1126.

6.
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 Comput. Biol. 2012, 8, e1002610.

7.
Cao, Z.; Mendoza, J.; Kozielski, A.; Liu, X.; Dejesus, A.; Wang, Y.; Zhan, C.-G.; Vardeman, D.; Giovanella, B. “Anticancer Activity of New Haloalkyl Camptothecin Esters against Human Cancer Cell Lines and Human Tumor Xenografts Grown in Nude Mice”, Anticancer Agents Med. Chem. 2012, 12, 818-828.

8.
Hamza, A.; Wei, N.-N.; Zhan, C.-G. “Ligand-based virtual screening approach using a new scoring function”, J. Chem. Inf. Modeling 2012, 52, 963-974.

9.
Lei, B.; Hamza, A.; Zhan, C.-G. “Structural features and binding free energies for non-covalent inhibitors interacting with immunoproteasome by molecular modeling and dynamics simulations”, Theo. Chem. Acc. 2012, 131, 1203.

10.
Liu, J.; Zhan, C.-G. “Reaction pathway and free energy profile for cocaine hydrolase-catalyzed hydrolysis of (–)-cocaine”, J. Chem. Theory Comput. 2012, 8, 1426-1435.

11.
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 2012, 116, 3361-3368.

12.
Chen, X.; Fang, L.; Liu, J.; Zhan, C.-G. “Reaction pathway and free energy profiles for butyrylcholinesterase-catalyzed hydrolysis of acetylthiocholine”, Biochemistry 2012, 51, 1297­1305.

13.
Yang, W.; AbdulHameed, M. D. M.; Hamza, A.; Zhan, C.-G. “New inhibitor of 3-phosphoinositide dependent protein kinase-1 identified from virtual screening”, Bioorg. Med. Chem. Letters 2012, 22, 1629-1632.

14.
Huang, X.; Zheng, G.; Zhan, C.-G. “Microscopic binding of M5 muscarinic acetylcholine receptor with antagonists by homology modeling, molecular docking and molecular dynamics simulation”, J. Phys. Chem. B 2012, 116, 532-541.

15.
Hamza, A.; Wei, N.-N.; Johnson-Scalise, T.; Naftolin, F.; Cho, H.; Zhan, C.-G. “Unveiling the unfolding pathway of F5F8D disorder-associated D81H/V100D mutant of MCFD2 via multiple molecular dynamics simulations”, J. Biomol. Struct. Dyn. 2012, 29, 699-714.

16.
Zheng, F.; Zhan, C.-G. “Are pharmacokinetic approaches feasible for treatment of cocaine addiction and overdose?”, Future Med. Chem. 2012, 4, 125-128.

17.
Yang, X.; Yuan, Y.; Zhan, C.-G.; Liao, F. “Uricases as therapeutic agents to treat refractory gout: Current states and future directions”, Drug Develop. Res. 2012, 73, 66-72.

18.
Carmony, K. C.; Lee, D. M.; Wu, Y.; Lee, N. R.; Wehenkel, M.; Lee, J.; Lei, B.; Zhan, C.-G.; Kim, K. B. “A bright approach to the immunoproteasome: Development of LMP2/ß1i-specific imaging probes”, Bioorg. Med. Chem. 2012, 20, 607-613.

19.
Bargagna-Mohan, P.; Paranthan, R. R.; Hamza, A.; Zhan, C.-G.; Lee, D.-M.; Kim, K.-B.; Lau, D. L.; Srinivasan, C.; Nakayama, K.; Nakayama, K. I.; Herrmann, H.; Mohan, R. “Corneal antifibrotic switch identified in genetic and pharmacological deficiency of Vimentin”, J. Biol. Chem. 2012, 287, 989-1006.

2011

1.
Chen, X.; Zhao, X.; Xiong, Y.; Liu, J.; Zhan, C.-G. “Fundamental reaction pathway and free energy profile for hydrolysis of intracellular second messenger adenosine 3',5'-cyclic monophosphate (cAMP) catalyzed by phosphodiesterase-4”, J. Phys. Chem. B 2011, 115, 12208-12219.

2.
Hamza, A.; Piao, Y.L.; Kim, M.S.; Choi, C.H.; Zhan, C.-G.; Cho, H. “Insight into the binding of the wild type and mutated alginate lyase (AlyVI) with its substrate: A computational and experimental study”, Biochim. Biophys. Acta 2011, 1814, 1739-1747.

3.
Hamza, A.; Zhao, X.; Tong, M.; Tai, H.-H.; Zhan, C.-G. “Novel human mPGES-1 inhibitors identified through structure-based virtual screening”, Bioorg. Med. Chem. 2011, 19, 6077-6086.

4.
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”, J. Phys. Chem. B 2011, 115, 11254-11260.

5.
Fang, L.; Pan, Y.; Muzyka, J.; Zhan, C.-G. “Active site gating and substrate specificity of butyrylcholinesterase and acetylcholinesterase: Insights from molecular dynamics simulations”, J. Phys. Chem. B 2011, 115, 8797-8805.

6.
AbdulHameed, M. D. M.; Li, H.; Pan, Y.; Silva-Rivera, C.; Zhan, C.-G. “Microscopic binding of butyrylcholinesterase with quinazolinimine derivatives and the structure-activity correlation”, Theo. Chem. Acc. 2011, 130, 69-82.

7.
Liu, J.; Zhao, X.; Yang, W.; Zhan, C.-G. “Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (–)-cocaine: Unexpected common rate-determining step”, J. Phys. Chem. B 2011, 115, 5017-5025.

8.
Huang, X.; Gao, D.; Zhan, C.-G. “High-temperature molecular dynamics simulation for rational design of a thermostable mutant of cocaine esterase”, Org. Biomol. Chem. 2011, 9, 4138-4143.

9.
Hill, E. R.; Huang, X.; Zhan, C.-G.; Carroll, F. I.; Gu, H. H. “Interaction of tyrosine 151 in norepinephrine transporter with the 2ß group of cocaine analog RTI-113”, Neuropharmacology 2011, 61, 112-120.

10.
Chen, X.; Fang, L.; Liu, J.; Zhan, C.-G. “Reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of acetylcholine”, J. Phys. Chem. B 2011, 115, 1315­1322.

11.
Zhan, C.-G. “Development and application of first-principles electronic structure approach for molecules in solution based on fully polarizable continuum model”, Acta Phys. Chim. Sin. 2011, 27, 1-10.

12.
Fairchild, S.Z.; Peterson, M.W.; Hamza, A.; Zhan, C.-G.; Cerasoli, D.M.; Chang, W.E. “Computational characterization of how the VX nerve agent binds human serum paraoxonase 1”, J. Mol. Model. 2011, 17, 97-109.

13.
Zheng, F.; Zhan, C.-G. “Enzyme therapy approaches for treatment of drug overdose and addiction”, Future Med. Chem. 2011, 3, 9-13.

14.
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”, Mol. Pharmacol. 2011, 79, 290-297.

15.
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.

2010

1.
Zheng, F.; Yang, W.; Xue, L.; Hou, S.; Liu, J.; Zhan, C.-G. “Design of high-activity mutants of human butyrylcholinesterase against (-)-cocaine: structural and energetic factors affecting the catalytic efficiency”, Biochemistry 2010, 49, 9113-9119.

2.
Bargagna-Mohan, P.; Paranthan, R. R.; Hamza, A.; Dimova, N.; Srinivasan, C.; Elliott, G. I.; Zhan, C.-G.; Lau, D.; Cambi, F.; Mohan, R. “Withaferin A targets intermediate filaments GFAP and vimentin in a model of retinal gliosis”, J. Biol. Chem. 2010, 285, 7657-7669.

3.
Yang, B.; Hamza, A.; Wang, Y.; Chen, G.; Zhan, C.-G. “Computational determination of binding structures and free energies of phosphodiesterase-2 with benzo1,4diazepin-2-one derivatives”, J. Phys. Chem. B 2010, 114, 16020-16028.

4.
Lei, B.; AbdulHameed, M. D. M.; Hamza, A.; Wehenkel, M.; Muzyka, J. L.; Yao, X.-J.; Kim, K.­B.; Zhan, C.-G. “Molecular basis of the selectivity of the immunoproteasome catalytic subunit LMP2-specific inhibitor revealed by molecular modeling and dynamics simulations”, J. Phys. Chem. B 2010, 114, 12333-12339.

5.
Huang, X.; Pan, Y.; Zheng, F.; Zhan, C.-G. “Reaction pathway and free energy profile for pre-chemical reaction step of human butyrylcholinesterase-catalyzed hydrolysis of (-)-cocaine by combined targeted molecular dynamics and potential of mean force simulations”, J. Phys. Chem. B 2010, 114, 13545-13554.

6.
Yang, W.; Pan, Y.; Fang, L.; Gao, D.; Zheng, F.; Zhan, C.-G. “Free-energy perturbation simulation on transition states and high-activity mutants of human butyrylcholinesterase for (-)-cocaine hydrolysis”, J. Phys. Chem. B 2010, 114, 10889-10896.

7.
Hao, G.-F.; Yang, G.-F.; Zhan, C.-G. “Computational mutation scanning and drug resistance mechanisms of HIV-1 protease inhibitors”, J. Phys. Chem. B 2010, 114, 9663-9676.

8.
Narasimhan, D.; Nance, M. R.; Gao, D.; Ko, M.-C.; Macdonald, J.; Tamburi, P.; Yoon, D.; Landry, D. M.; Woods, J. H.; Zhan, C.-G.; Tesmer, J. J. G.; Sunahara, R. K. “Structural analysis of
thermostabilizing mutations of cocaine esterase”, Protein Eng. Des. Sel. 2010, 23, 537-547.


9.
Yang, W.; Xue, L.; Fang, L.; Zhan, C.-G. “Characterization of a high-activity mutant of human butyrylcholinesterase against (-)-cocaine”, Chemico-Biological Interactions 2010, 187, 148-152.

10.
Li, D.; Wang, Y.; Han, K.; Zhan, C.-G. “Fundamental Reaction Pathways for Cytochrome P450­catalyzed 5.-Hydroxylation and N-Demethylation of Nicotine”, J. Phys. Chem. B 2010, 114, 9023­9030.

11.
Lu, H.; Goren, A. C.; Zhan, C.-G. “Characterization of the structures of phosphodiesterase 10 binding with adenosine 3´,5´-monophosphate and guanosine 3´,5´-monophosphate by hybrid quantum mechanical/molecular mechanical calculations”, J. Phys. Chem. B 2010, 114, 7022-7028.

12.
Zhao, X.; Chen, X.; Yang, G.-F.; Zhan, C.-G. “Structural assignment of 6-oxy purine derivatives through computational modeling, synthesis, X-ray diffraction, and spectroscopic analysis”, J. Phys. Chem. B 2010, 114, 6968-6972.

13.
Hamza, A.; Tong, M.; AbdulHameed, M. D. M.; Li, H.; Goren, A. C.; Tai, H.-H.; Zhan, C.-G. “Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: Insights from computational alanine scanning and site-directed mutagenesis”, J. Phys. Chem. B 2010, 114, 5605-5616.

14.
Liu, J.; Kelly, C. P.; Goren, A. C.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G.; Zhan, C.-G. “Free energies of solvation with surface, volume, and local electrostatic effects and atomic surface tensions to represent the first solvation shell”, J. Chem. Theory Comput. 2010, 6, 1109-1117.

15.
Brim, R. L.; Nance, M. R.; Youngstrom, D. W.; Narasimhan, D.; Zhan, C.-G.; Tesmer, J. J. G.; Sunahara, R. K.; Woods, J. H. “A thermally stable form of bacterial cocaine esterase: A potential therapeutic agent for treatment of cocaine abuse”, Mol. Pharmacol. 2010, 77, 593-600.

16.
Xiong, Y.; Liu, J.; Yang, G.-F.; Zhan, C.-G. “Computational determination of fundamental pathway and free energy barriers for acetohydroxyacid synthase-catalyzed condensation reactions of .-keto acids”, J. Comput. Chem. 2010, 31, 1592-1602.

17.
Yu, Y.; Hamza, A.; Zhang, T.; Gu, M.; Zou, P.; Newman, B.; Li, Y.; Gunatilaka, A.A.; Whitesell, L.; Zhan, C.-G.; Sun, D. “Withaferin A targets heat shock protein 90 in pancreatic cancer cells”, Biochem. Pharmacol. 2010, 79, 542-551.

18.
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.

2009

1.
Liu, J.; Zhang, Y.; Zhan, C.-G. “Fundamental dephosphorylation mechanism of dimethylphosphonyl-inhibited human acetylcholinesterase”, J. Phys. Chem. B 2009, 113, 16226­16236.

2.
Huang, X.; Gu, H.; Zhan, C.-G. “Mechanism for cocaine blocking the transport of dopamine: Insights from molecular modeling and dynamics simulations”, J. Phys. Chem. B 2009, 113, 15057­15066.

3.
Zheng, F.; Dwoskin, L. P.; Crooks, P. A.; Zhan, C.-G. “First-principles determination of molecular conformations of indolizidine (-)-235B' in solution”, Theo. Chem. Acc. 2009, 124, 269-278.

4.
Zhu, X.-L.; Hao, G.-F.; Zhan, C.-G.; Yang, G.-F. “Computational simulations of the interactions between acetyl-coenzyme-A carboxylase and clodinafop: Resistance mechanism due to active and nonactive site mutations”, J. Chem. Inf. Modeling 2009, 49, 1936-1943.

5.
Zheng, F.; Zhan, C.-G. “Recent progress in protein drug design and discovery with a focus on novel approaches to the development of anti-cocaine medications”, Future Med. Chem. 2009, 1, 515-528.

6.
Zheng, F.; McConnell, M.J.; Zhan, C.-G.; Dwoskin, L.P.; Crooks, P.A. “QSAR study on maximal inhibition (Imax) of quaternary ammonium antagonists for S-(-)-nicotine-evoked dopamine release from dopaminergic nerve terminals in rat striatum”, Bioorg. Med. Chem. 2009, 17, 4477-4485.

7.
Pan, Y.; Muzyka, J.; Zhan, C.-G. “Model of human butyrylcholinesterase (BChE) tetramer by homology modeling and dynamics simulation”, J. Phys. Chem. B 2009, 113, 6543-6552.

8.
Hao, G.-F.; Zhu, X.-L.; Ji, F.-Q.; Yang, G.-F.; Zhan, C.-G. “Understanding mechanism of drug resistance due to a codon deletion in protoporphyrinogen oxidase through computational modeling”, J. Phys. Chem. B 2009, 113, 4865-4875.

9.
Yang, W.; Pan, Y.; Zheng, F.; Cho, H.; Tai, H.-H.; Zhan, C.-G. “Free energy perturbation (FEP) simulation on transition states and design of high-activity mutants of human butyrylcholinesterase for accelerating cocaine metabolism”, Biophysical Journal 2009, 96, 1931-1938.

10.
Hamza, A.; Zhan, C.-G. “Determination of the structure of human phosphodiesterase-2 in a bound state and its binding with inhibitors by molecular modeling, docking, and dynamics simulation”, J. Phys. Chem. B 2009, 113, 2896-2908.

11.
Zhu, Y; Wang, Y.; Chen, G.; Zhan, C.-G. “Evaluations of classical AMBER force field parameters for copper-based artificial nucleases”, Theor. Chem. Acc. 2009, 122, 167–178.

12.
Zheng, F.; Zheng, G.; Deaciuc, A. G.; Zhan, C.-G.; Dwoskin, L. P.; Crooks, P. A. “Computational neural network analysis of the affinity of n-n-alkyl nicotinium salts for the a4ß2* nicotinic acetylcholine receptor”, J. Enzy. Inhib. Med. Chem. 2009, 24, 157-168.

13.
Zhao, X.; Chen, X.; Zhan, C.-G. “Advances in the structure of phosphodiesterase 2 and selective inhibitors”, Chinese J. Org. Chem . 2009, 29, 159-165.

14.
Zhan, C.-G. “Novel pharmacological approaches to treatment of drug overdose and addiction”, Expert Rev. Clinical Pharmacol. 2009, 2, 1-4.

15.
Gao, D.; Narasimhan, D. L.; Macdonald, J.; Ko, M.-C.; Landry, D. W.; Woods, J. H.; Sunahara, R. K.; Zhan, C.-G. “Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity”, Mol. Pharmacol. 2009, 75, 318-323.

16.
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.

2008

1.
Huang, X.; Zheng, F.; Stokes, C.; Papke, R. L.; Zhan, C.-G. “Modeling binding modes of .7 nicotinic acetylcholine receptor with ligands: the roles of Gln117 and other residues of the receptor in agonist binding”, J. Med. Chem. 2008, 51, 6293-6302.

2.
Vilkas, M. J.; Zhan, C.-G. “An efficient implementation for determining volume polarization in self-consistent reaction field theory”, J. Chem. Phys. 2008, 129, 194109.

3.
Chen, X.; Zhan, C.-G. “First-principles determination of molecular conformations of cyclic adenosine 3.,5.-monophosphate in gas phase and aqueous solution”, J. Phys. Chem. B 2008, 112, 16851-16859.

4.
AbdulHameed, M. D. M.; Hamza, A.; Zhan, C.-G. “Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1 (PDK1)”, J. Chem. Inf. Modeling 2008, 48, 1760-1772.

5.
Ji, F.-Q.; Chen, C.-N.; Chen, Q.; Yang, G.-F.; Niu, Q.-W.; Xi, Z.; Zhan, C.-G. “Modeling computational design and discovery of conformationally flexible inhibitors of acetohydroxyacid synthase to overcome drug resistance associated with W586L mutation”, ChemMedChem. 2008, 3, 1203-1206.

6.
Xiong, Y.; Lu, H.-T.; Zhan, C.-G. “Dynamic structures of phosphodiesterase-5 active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations”, J. Comput. Chem. 2008, 29, 1259-1267.

7.
AbdulHameed, M. D. M.; Hamza, A.; Liu, J.; Huang, X.; Zhan, C.-G. “Human microsomal prostaglandin E synthase-1 (mPGES-1) binding with inhibitors and the quantitative structure-activity correlation”, J. Chem. Inf. Modeling 2008, 46, 179-185.

8.
Zheng, F.; Zhan, C.-G. “Rational design of an enzyme mutant for anti-cocaine therapeutics” (invited review), J. Computer-Aided Mol. Design, 2008, 22, 661-671.

9.
Li, Q.; Wei, Y.; Guo, H.; Zhan, C.-G. “Syntheses, structural characterizations and electronic absorption spectra simulation of three phenylimido substituted hexamolybdates incorporating a remote chloro group”, Inorg. Chim. Acta 2008, 361, 2305-2313.

10.
Zheng, F.; Zhan, C.-G. “Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose” (invited perspective), Org. Biomol. Chem. 2008, 6, 836-843.

11.
Zhan, C.-G. “Speeding up cocaine” (invited “Instant Insight”), Chemical Science. 2008, 3 (11 Feb. 2008) (http://www.rsc.org/Publishing/ChemScience/Volume/2008/03/Speeding_up_cocaine.asp).

12.
Zhang, T.; Hamza, A. Cao, X.; Wang, B.; Yu, S.; Zhan, C.-G.; Sun, D. “A novel Hsp90 inhibitor disrupts Hsp90/Cdc37 complex for pancreatic cancer therapy”, Molecular Cancer Therapeutics 2008, 7, 162-170 (Cover article).

13.
Hamza, A.; AbdulHameed, M. D. M.; Zhan, C.-G. “Understanding microscopic binding of human microsomal prostaglandin e synthase-1 (mPGES-1) with substrates and inhibitors by molecular modeling and dynamics simulation”, J. Phys. Chem. B 2008, 112, 7320-7329 (Cover article).

14.
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.

15.
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.

16.
Huang, X.; Zheng, F.; Zhan, C.-G. “Modeling Differential Binding of .4.2 Nicotinic Acetylcholine Receptor with Agonists and Antagonists”, J. Am. Chem. Soc. 2008, 130, 16691­16696.

Center for Computational Sciences