Fragment-based lead discovery: a chemical update.
Fragment-based lead discovery constructs drug leads from small molecular fragments. In theory, this is a highly efficient method for drug discovery, and the technique has become enormously popular in the past few years. In this review, I describe how a variety of approaches in fragment-based lead discovery--including NMR, X-ray crystallography, mass spectrometry, functional screening, and in silico screening--have produced drug leads. Although the examples show that the technique can reliably generate potent molecules, there is still much work to be done to maintain the efficiency of molecules' binding affinities as fragments are linked, expanded, and otherwise improved.
Erlanson
Daniel A
DA
Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. erlanson@sunesis.com
D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D008956:Models, Chemical; D008961:Models, Structural; D011506:Proteins / Q000737:chemistry* / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D011506:Proteins