title: Second-site NMR screening and linker design.
abstract: 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 Published examples from second-site screening and linker design are summarized, and are complemented by previously unpublished in-house examples.
authors.affiliation: Novartis Pharma AG, Central Technologies and Oncology Research, CH-4002 Basel, Switzerland. wolfgang.jahnke@pharma.novartis.com
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
authors.forename: Andreas
authors.initials: A
authors.lastname: Flörsheimer
authors.forename: Marcel J J
authors.initials: MJ
authors.lastname: Blommers
authors.forename: C Gregory
authors.initials: CG
authors.lastname: Paris
authors.forename: Jutta
authors.initials: J
authors.lastname: Heim
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Nalin
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Perez
mesh_terms: 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
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins; D013113:Spin Labels