Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly.
Rapid progress in genomics and proteomics has provided a wealth of new targets for the pharmaceutical industry, even as many older targets still remain challenging for small-molecule drug discovery. Fragment-based lead discovery, in which leads are built progressively by expanding or combining small fragments, is a rapidly growing field that offers potential advantages over traditional lead-discovery processes. However, identifying and assembling the fragments themselves can be challenging. Here, we review the concept of site-directed ligand discovery, in which a covalent bond is used to stabilize the interaction between a low-affinity fragment and a target protein. We also describe how this technique can facilitate fragment-based lead discovery and help overcome some of the limitations of traditional screening methods.
Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, California 94080, USA. erlanson@sunesis.com
Daniel A
DA
Erlanson
Stig K
SK
Hansen
D001665:Binding Sites / Q000502:physiology; D015195:Drug Design; D008024:Ligands; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D010446:Peptide Fragments; D011506:Proteins