title: A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors.
abstract: The increasing diversity of small molecule libraries has been an important source for the development of new drugs and, more recently, for unraveling the mechanisms of cellular events-a process termed chemical genetics.(1) Unfortunately, the majority of currently available compounds are mechanism-based enzyme inhibitors, whereas most of cellular activity regulation proceeds on the level of protein-protein interactions. Hence, the development of small molecule inhibitors of protein-protein interactions is important. When screening compound libraries, low-micromolar inhibitors of protein interactions can be routinely found. The enhancement of affinities and rationalization of the binding mechanism require structural information about the protein-ligand complexes. Crystallization of low-affinity complexes is difficult, and their NMR analysis suffers from exchange broadening, which limits the number of obtainable intermolecular constraints. Here we present a novel method of ligand validation and optimization, which is based on the combination of structural and computational approaches. We successfully used this method to analyze the basis for structure-activity relationships of previously selected (2) small molecule inhibitors of the antiapoptotic protein Bcl-xL and identified new members of this inhibitor family.
authors.affiliation: Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Lugovskoy
authors.forename: Alexei I
authors.initials: AI
authors.lastname: Degterev
authors.forename: Amr F
authors.initials: AF
authors.lastname: Fahmy
authors.forename: Pei
authors.initials: P
authors.lastname: Zhou
authors.forename: John D
authors.initials: JD
authors.lastname: Gross
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D051020:bcl-X Protein
chemical_list: D000085:Acetates; D001549:Benzamides; D001597:Benzylidene Compounds; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein