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    Jie Zheng, PhD

    Jie Zheng, PhD

    Virtual drug development occurs at molecular level

    St. Jude researchers demonstrated that it is feasible to use a computer-based virtual drug screening approach to identify compounds that have just the right chemical structure to block a specific tumor-promoting molecule.

    The investigators identified an organic molecule obtained from the National Cancer Institute’s small-molecule library as suitable for binding to Dishevelled (Dvl), a critical protein in a signaling pathway called Wnt.

    Wnt pathways are involved in the multiplication of cells that drives normal embryonic development, as well as in pathways involved in tumor formation. A report on this work appears in the November online issue of Biochemistry.

    Wnt triggers either of the two signaling pathways by binding to a receptor called Frizzled (Fz) on the surface membrane of cells. This activates Dvl proteins inside the cell which, in turn, activates a series of other reactions. The final step in this complex series of biochemical reactions is the transcription (activation) of specific genes in the nucleus that are the target of the initial Wnt signal. In the case of tumors, this includes Myc and other cancer genes.

    Using a technique called NMR-assisted in silico process, the St. Jude team determined that the molecule NSC668036 can bind to Dvl, and then be analyzed on a molecular level. The researchers showed that NSC668036 can block the activity of Dvl by binding to a part of Dvl called PDZ. Specifically, they showed that by binding to PDZ, NSC668036 disrupts normal growth of a laboratory model of a frog embryo that depends on Dvl to develop normally.

    “This work is important because it showed that it is possible to use virtual drug screening in combination with our structural biology studies to find novel agents that could become anti-cancer drugs,” said Jie Zheng, PhD, Structural Biology. “Our technique seems to work very well. Since the original report, we now have identified more inhibitors. This method certainly gives us a powerful drug development tool.”

    The other St. Jude author of this paper is Jufang Shan, a graduate student working in Zheng’s laboratory.

    Most of the computational work was performed using the scientific computing facility at the Hartwell Center. “We really owe a big thank you to Scott Malone, a systems integration engineer at the Hartwell Center, for his enormous technical support during the course of this study,” Zheng said.


    Last update: February 2006