The SHAPES strategy: an NMR-based approach for lead generation in drug discovery.
BACKGROUND
Recently, it has been shown that nuclear magnetic resonance (NMR) may be used to identify ligands that bind to low molecular weight protein drug targets. Recognizing the utility of NMR as a very sensitive method for detecting binding, we have focused on developing alternative approaches that are applicable to larger molecular weight drug targets and do not require isotopic labeling.


RESULTS
A new method for lead generation (SHAPES) is described that uses NMR to detect binding of a limited but diverse library of small molecules to a potential drug target. The compound scaffolds are derived from shapes most commonly found in known therapeutic agents. NMR detection of low (microM-mM) affinity binding is achieved using either differential line broadening or transferred NOE (nuclear Overhauser effect) NMR techniques.


CONCLUSIONS
The SHAPES method for lead generation by NMR is useful for identifying potential lead classes of drugs early in a drug design program, and is easily integrated with other discovery tools such as virtual screening, high-throughput screening and combinatorial chemistry.
Fejzo
J
J
Vertex Pharmaceuticals Incorporated 130 Waverly Street, Cambridge, MA 02139-4242, USA.
Lepre
C A
CA
Peng
J W
JW
Bemis
G W
GW
Ajay
Murcko
M A
MA
Moore
J M
JM
D007168:IMP Dehydrogenase / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008970:Molecular Weight; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D013678:Technology, Pharmaceutical; D048051:p38 Mitogen-Activated Protein Kinases
D008024:Ligands; D019151:Peptide Library; D007168:IMP Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases