School of Pharmacy

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Shijun Zhang, Ph.D.
Professor
Department of Medicinal Chemistry
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  •   BioTech One, Suite 205, Room 251g
  • School of Pharmacy - Dept of Medicinal Chemistry
    BioTech One, Suite 205
    800 E. Leigh St.
    Box 980540
     Richmond, VA 23298-0540
  •  (804) 628-8266
    (804) 828-7625
  •  szhang2@vcu.edu

Area of Focus

  • Small molecule design and development for neurodegenerative and inflammatory disorders

Education

  • Ph.D., Pharmaceutical Sciences (Wayne State University, 2004)

Post-Graduate Training

  • Postdoctoral Fellow - Medicinal Chemistry (University of Minnesota, 2007)

Professional Experience

  • (2019 - Present) Professor, Department of Medicinal Chemistry, VCU
  • (2014 - 2019) Associate Professor, Department of Medicinal Chemistry
  • (2007 - 2014) Assistant Professor, Department of Medicinal Chemistry, VCU
  • (2005 - 2007) Research Associate, Department of Medicinal Chemistry, University of Minnesota

Research Interests

  • 1. Design and development of novel multifunctional ligands as pharmacological tools and potential disease-modifying agents for Alzheimer's disease. Multiple pathogenic factors such as beta-amyloid, oxidative stress, biometals and neuroinflammation have been implicated in the development of AD. Furthermore cell membrane/lipid rafts have been shown to play a critical role in the pathogenisis of AD, thus indicating the relationship of cell membrane/lipid rafts with other risk factors can be exploited therapeutically. One of our research interests focuses on the development of multifunctional bivalent lignads that bridge cell membrane/lipid rafts and beta-amyloid oligomers, oxidative stress, and bimetals simultaneously. The research involves rational design, organic synthesis, in vitro and in vivo biological charaterization. Another direction is focused on the development of hybrid molecules of curcumin, thalidomide, and melatonin as lead compounds to develop multifunctional ligands with a emphasis on neuroinflammation and neurotrophic function.
  • 2. Design and development of selective sphingosine kinase inhibitors as pharmacological tools and exploration of their potential clinical applications. Sphingosine kinases (SphK1 and SphK2) are responsible for the production of S1P, a lipid metabolite that has been recognized as an important signaling mediator for vital cellular and physiological processes. Although SphK1 and SphK2 share a high degree of homology, they have significant differences in size, tissue distribution, and subcellular localization, among others. For example, SphK1 mainly resides in the cytosol while SphK2 is present in several intracellular compartments, mainly in the nucleus, endoplasmic reticulum, and mitochondria. Accumulating evidence have indicated the involvement of SphKs in a variety of pathological conditions such as cancer, asthama, immune reaction and Alzheimer's disease. Therefore, development of selective SphK inhibitors would be of great value as pharmacological tools to help unravel the roles of these SphKs, especially development of SphK2 selective inhibitors given the fact that highly selective and potent SphK2 inhibitors remain scarce. One project is focused on the development of thiazolidine-2,4-dione and oxindole analogs as selective SphK2 inhibitors. Another project is focused on the development of sphingosine analogs as selective SphK1 inhibitors. The techniques employed in these projects include organic synthesis, in vitro assays using various cancer cell lines, biochemical assays using recombinant SphK1 and SphK2, and in vivo studies using mice and rat.
  • 3. Design and development of dual-pathway inhibitors. Deregulation of signaling pathways have been indicated to play important roles in the tumorigenity and drug resistance of human cancers, among which the Raf/MEK/ERK and the PI3K/Akt pathways have been well characterized. We are particularly interested in developing dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways as chemical tools and potential anticancer agents. Recently we have idnetified several lead ligands that possess such dual inhibiton properties and extensive SAR studies are undertaking to optimize the biological activity. This project invovles organic synthesis, molecular modeling, in vitro and in vivo screening using cancer models.
  • 4. Molecular modeling studies. Molecular modeling studies are intended to act synergistically with the synthetic and bioassay teams in validating and rationalizing assay results in terms of structural features of the tested inhibitors. In our aforementioned studies, molecular modeling studies have been incorporated to faciliatet the identification of new lead compounds. Specifically we will use 2D and 3D QSAR to explore the structure-activity relationship studies. Docking studies are also widely applied to shed light on the interactions with interested protein targets.

Publications

Books/Book Chapters

  • 1. Xu, Wenfang; Zhao, Guisen; Zhang, Shijun. “The Principles and Methods of New Drug Design” 1st Edition, China Medical Science and Technology Publishing House, Jul. 1997 2. Xu, Wenfang; Zhao, Guisen; Zhang, Shijun. “The Principles and Methods of New Drug Design” 2d Edition, Science Publishing House, Oct. 2000

Recent Publications

  • Lenhart, J.A.; Ling, X.; Gandhi, R.; Guo, T.L.; Gerk, P.M.; Brunzell, D.H.; Zhang, S. "Clicked" Bivalent Ligands Containing Curcumin and Cholesterol As Multifunctional Abeta Oligomerization Inhibitors: Design, Synthesis, and Biological Characterization. J. Med. Chem. 2010, 53, 6198-6209.
  • Li, Q.; Wu, J.; Zheng, H.; Liu, K.; Guo, T.L.; Liu, Y.; Eblen, S.T.; Grant, S.; Zhang, Shijun. Discovery of 3-(2-aminoethyl)-5-(3-phenyl-propylidene)-thiazolidine-2,4-dione as a dual inhibitor of the Raf/MEK/ERK and the PI3K/Akt signaling pathways. Bioorg. & Med. Chem. Lett. 2010, 20, 4526-4530.
  • Zhang, Shijun; Yekkirala, Ajay; Tang, Ye; Portoghese, Philip S. A bivalent ligand (KMN-21) antagonist for µ/? heterodimeric opioid receptors. Bioorg & Med. Chem. Lett. 2009, 19, 6978-6980.
  • Li, Qianbin; Al-Ayoubi, Adnan; Guo, Tailiang; Zheng, Hui; Sarkar, Aurijit; Nguyen, Tri; Eblen, Scott T.; Grant, Steven; Kellogg, Glen E.; Zhang, Shijun. Structure-activity relationship (SAR) studies of 3-(2- amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione: Development of potential substrate-specific ERK1/2 inhibitors. Bioorg & Med. Chem. Lett. 2009, 19, 6042-6046.
  • Zhang, Shijun; Fernandez, Fernando; Zhen, Juan; Reith, Maarten E. A.; Dutta, Aloke K.. Further structural exploration of tri-substituted asymmetric pyran derivaives, (2S, 4R, 5R)-2-benzhydryl-5- benzylamino-tetrahydropyran-4-ol and their corresponding disubstituted (3S, 6S)-pyran derivatives: A proposed pharmacohpore model for high affinity interaction with the dopamine, serotonin, and norepinephrine transporters. J. Med. Chem. 2006, 49, 4239-4237.
  • Zhang, Shijun; Zhen, Juan; Reith, Maarten E. A.; Dutta, Aloke K.. Design, Synthesis, and Preliminary SAR Study of 3-and 6-Sides-Chain Extended Tetrahydro-Pyran Analogues of cis- and trans-(6- benzhydryl-piperidin-3-yl)-benzylamine. Bioorg. & Med. Chem. 2006, 14, 3953- 3966.
  • Zhang, Shijun; Zhen, Juan; Reith, Maarten E.A.; Dutta, Aloke K.. Discovery of novel tri-substituted asymmetric pyran derivatives, (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol, exhibiting high affinity for serotonin and norepinephrine transporters in a stereospecific manner. J. Med. Chem. 2005, 48, 4962-4971.
  • Zhang, Shijun; Zhen, Juan; Reith, Maarten E.A.; Dutta, Aloke K.. Structural requirements for 2,4- and 3,6-disubstituted pyran biomimetics of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine compounds to interact with monoamine transporters. Bioorg. & Med. Chem. 2004, 12, 6301- 6315.
  • Dutta, Aloke K.; Venkataraman, Sylesh K.; Fei, Xiang-shu; Kolhatkar, Rohit; Zhang, Shijun; Reith,Maarten E.A.. Synthesis and biological characterization of novel hybrid 7-{[2-(4-phenylpiperazin- 1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol analogues for the dopamine D2 and D3 receptors. Bioorg. & Med. Chem. 2004, 12, 4361- 4373.
  • Dutta, Aloke K.; Zhang, Shijun; Kohhatkar, Rohit; Reith, Maarten E.A.. Dopamine Transporter as Target for Drug Development of Cocaine Dependence Medications. Europ. J. Pharmacol. 2003, 479, 93-106.
  • Zhang, Shijun; Reith, Maarten E.A.; Dutta, Aloke K.. Design, synthesis, and activity of novel cis- and trans-3,6-disubstituted pyran biomimetics of 3,6-disubstituted piperidine as potential ligands for the dopamine transporter. Bioorg. & Med. Chem. Lett. 2003, 13, 1591-1595.
  • Liu, Kai; Guo, Tai L.; Chojnacki, Jeremy; Lee, Hyoung-gon; Wang, Xianglong; Siedlak, Sandra L.; Rao, Wei; Zhu, Xiongwei; Zhang, Shijun. Bivalent ligand containing curcumin and cholesterol as fluorescence probe for Abeta plaques in Alzheimer's disease. ACS Chem. Neurosci. 2012, ASAP
  • Liu, Kai; Rao, Wei; Parikh, Hardik; Guo, Tai L.; Grant, Steven; Kellogg, Glen E.; Zhang, Shijun. 3,5-Disubstituted-thiazolidine-2,4-dione analogs as anticancer agents: Design, synthesis and biological characterization. Eur. J. Med. Chem. 2012, 47, 125-137.