title: Ligand specificity in fragment-based drug design.
abstract: Fragment-based drug design consists of identifying low-molecular weight compounds that weakly bind to a target macromolecule and will then be modified or linked to yield potent inhibitors. The specificity of these low-complexity and low-affinity molecules has rarely been discussed in the literature. To address this question, NMR spectroscopy was used to investigate the interactions of 150 fragments with five proteins: three proteins from the Bcl-2 family (Bcl-x(L), Bcl-w, and Mcl-1), human peroxiredoxin 5, for which very few ligands have been reported, and human serum albumin, which is known to bind a large number of ligands. Our results show that the fragments are rather versatile binders and able to identify binding hot spots in very different targets. Despite the different hit rates observed related to the druggability of the proteins, two scaffolds appear as preferred binders for all proteins. Low specificity was observed between homologous proteins or unrelated poorly druggable proteins, while higher specificity could be achieved with highly druggable targets.
authors.affiliation: Laboratoire des Sciences Analytiques, UMR CNRS 5180, Universite de Lyon, Universite Claude Bernard, Lyon 1, Bat. ESCPE Lyon, Domaine Scientifique de la Doua, 69100 Villeurbanne, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Barelier
authors.forename: Julien
authors.initials: J
authors.lastname: Pons
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lancelin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Krimm
mesh_terms: D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D054464:Peroxiredoxins / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D019253:Proto-Oncogene Proteins c-bcl-2; D012709:Serum Albumin; C515974:PRDX5 protein, human; D054464:Peroxiredoxins