Diversity-Oriented Synthesis and Rational Drug Design for Chemical Biology and Drug Discovery Research

Natural product-based strategies for chemical biology and drug discovery Enlarge Image Novel Probes for Chemical Biology and Drug Discovery Natural product-based design strategies are used at multiple levels Research in the Tan Lab focuses on synthetic organic chemistry and its applications to current challenges in chemical biology and drug discovery.

In the area of rational drug design, we are developing small molecule inhibitors that target adenylation enzymes, a mechanistic superfamily that is involved in a wide range of biological processes implicated in human diseases. We use mechanistic and structural information about individual targets of interest to design small molecule inhibitors, leveraging a natural product-based sulfonyladenosine design platform. Among these are novel antibiotics that inhibit bacterial biosynthesis of siderophores, menaquinone, and phenolic glycolipids. Semisynthetic protein-based inhibitors of eukaryotic E1 activating enzymes have also revealed striking enzyme remodeling during the conjugation of ubiquitin and other ubiquitin-like modifers to target proteins. We leverage synergistic multidisciplinary collaborations with biologists in our Tri-Institutional Research program and at other institutions to pursue these efforts.

We are also engaged in a complementary program in diversity-oriented synthesis, in which we are developing new synthetic routes and strategies to access small molecules that contain key structural motifs found in biologically active natural products. These efforts provide exciting opportunities to develop new synthetic methodologies and fundamental insights into chemical reactivity. Efficient, flexible synthetic routes are used to generate natural product-based libraries that access regions of chemical space not addressed by conventional drug-like libraries. These natural product-based libraries are being screened against a wide range of promising new therapeutic targets through collaborations with other labs in the Tri-Institutional Research Program, the Broad Institute, and the NIH Molecular Libraries Initiative.

More information about individual projects is available below.

Derek's talk at the National Academy of Sciences U.S. Kavli Frontiers of Science Symposium on Nov 12, 2009 is available online. This 30-minute Flash presentation gives an overview of our research for a general scientific audience.

ProgramAbstract (PDF)VideoVimeo Mirror ]

Key Review Articles

  1. Expanding the range of ‘druggable’ targets with natural product-based libraries: An academic perspective.
    Bauer, R. A.; Wurst, J. M.; Tan, D. S.* Curr. Opin. Chem. Biol. 2010, 14, 308–314.
    Abstract | PubMed | PMC ]
  2. Small molecule inhibition of microbial natural product biosynthesis – An emerging antibiotic strategy.
    Cisar, J. S.; Tan, D. S.* Chem. Soc. Rev. 2008, 37, 1320–1329.
    Abstract | PubMed | PMC ]
  3. Diversity-oriented synthesis: Exploring the intersections between chemistry and biology.
    Tan, D. S.* Nat. Chem. Biol. 2005, 1, 74–84.
    Abstract | PubMed ]

Research Projects