title: Fragment-based deconstruction of Bcl-xL inhibitors.
abstract: Fragment-based drug design consists of screening low-molecular-weight compounds in order to identify low-affinity ligands that are then modified or linked to yield potent inhibitors. The method thus attempts to build bioactive molecules in a modular way and relies on the hypothesis that the fragment binding mode will be conserved upon elaboration of the active molecule. If the inverse process is considered, do the fragments resulting from the deconstruction of high-affinity inhibitors recapitulate their binding mode in the large molecule? Few studies deal with this issue. Here, we report the analysis of 22 fragments resulting from the dissection of 9 inhibitors of the antiapoptotic protein Bcl-x(L). To determine if the fragments retained affinity toward the protein and identify their binding site, ligand-observed and protein-observed NMR experiments were used. The analysis of the fragments behavior illustrates the complexity of low-affinity protein-ligand interactions involved in the fragment-based construction of bioactive molecules.
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: Olivier
authors.initials: O
authors.lastname: Marcillat
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lancelin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Krimm
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009930:Organic Chemicals / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: C494811:BCL2L1 protein, human; D008024:Ligands; D009930:Organic Chemicals; D011994:Recombinant Proteins; D051020:bcl-X Protein