Abstract
Fragment-based ligand design (FBLD) approaches have become more widely used in drug discovery projects from both academia and industry, and are even often preferred to traditional high-throughput screening (HTS) of large collection of compounds (>105). A key advantage of FBLD approaches is that these often rely on robust biophysical methods such as NMR spectroscopy for detection of ligand binding, hence are less prone to artifacts that too often plague the results from HTS campaigns. In this article, we introduce a screening strategy that takes advantage of both the robustness of protein NMR spectroscopy as the detection method, and the basic principles of combinatorial chemistry to enable the screening of large libraries of fragments (>105 compounds) preassembled on a common backbone. We used the method to identify compounds that target protein-protein interactions.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 19-33 |
| Number of pages | 15 |
| Journal | Chemistry and Biology |
| Volume | 20 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 24 2013 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank the NIH for generous support (Grant NIDA 1R01DA031370-01 to R.A.H. and M.G.; Multiple Sclerosis National Research Institute to C.P.; and partially funded by the State of Florida, Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development to R.A.H. and M.G.; Grant NCI P01CA138390 to E.B.P. and M.P.). We also thank Dr. Jianxing Song and Dr. Haina Qin at the University of Singapore for kindly sharing the expression plasmid for EphA4. Finally, we thank Dr. Andrey Bobkov of the SBMRI Protein Analysis Facility for precious support with ITC measurements. M.P. is a founder of AnCoreX Therapeutics, LLC and a member of its scientific advisory board.
