Second-site NMR screening and linker design.
One of the prime merits of NMR as a tool for lead finding in drug discovery research is its sensitivity and robustness to detect weak protein-ligand interactions. This sensitivity allows to build up ligands for a given target in a modular way, by a fragment-based approach. In this approach, two ligands are seperately identified which bind to the target protein generally weakly, but at adjacent binding sites. In a next step, they are chemically linked to produce a high-affinity ligand. This review discusses methods to detect "second-site" ligands that bind to a protein in the presence of a "first-site" ligand, and methods to elucidate structural details on the spatial orientation of both ligands, so that chemical linkage is based on a large piece of experimental information. Published examples from second-site screening and linker design are summarized, and are complemented by previously unpublished in-house examples.
Jahnke
Wolfgang
W
Novartis Pharma AG, Central Technologies and Oncology Research, CH-4002 Basel, Switzerland. wolfgang.jahnke@pharma.novartis.com
Flörsheimer
Andreas
A
Blommers
Marcel J J
MJ
Paris
C Gregory
CG
Heim
Jutta
J
Nalin
Carlo M
CM
Perez
Lawrence B
LB
D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013113:Spin Labels
D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins; D013113:Spin Labels