Privileged molecules for protein binding identified from NMR-based screening.
A statistical analysis of NMR-derived binding data on 11 protein targets was performed to identify molecular motifs that are preferred for protein binding. The analysis indicates that compounds which contain a biphenyl substructure preferentially bind to a wide range of proteins and that high levels of specificity (>250-fold) can be achieved even for these small molecules. These results suggest that high-throughput screening libraries that are enriched with biphenyl-containing compounds can be expected to have increased chances of yielding high-affinity ligands for proteins, and they suggest that the biphenyl can be utilized as a template for the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets.
Hajduk
P J
PJ
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Bures
M
M
Praestgaard
J
J
Fesik
S W
SW
D001713:Biphenyl Compounds / Q000737:chemistry*; D016208:Databases, Factual; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D008024:Ligands; D011506:Proteins