HTS by NMR of combinatorial libraries: a fragment-based approach to ligand discovery.
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 (>10(5)). 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 (>10(5) compounds) preassembled on a common backbone. We used the method to identify compounds that target protein-protein interactions.
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bainan
B
Wu
Ziming
Z
Zhang
Roberta
R
Noberini
Elisa
E
Barile
Marc
M
Giulianotti
Clemencia
C
Pinilla
Richard A
RA
Houghten
Elena B
EB
Pasquale
Maurizio
M
Pellecchia
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D036122:Receptor, EphA4 / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D054852:Small Molecule Libraries; D051636:X-Linked Inhibitor of Apoptosis Protein; D036122:Receptor, EphA4