title: Molecular dynamics study of peptide segments of the BH3 domain of the proapoptotic proteins Bak, Bax, Bid and Hrk bound to the Bcl-xL and Bcl-2 proteins.
abstract: Overexpression of Bcl-2 and Bcl-xL proteins, both inhibitors of apoptosis or programmed cell death, is related to the generation and development of several types of cancer as well as to an elevated resistance to chemotherapeutic treatments. Given that synthetic peptide fragments of the BH3 domain are capable to bind to both proteins and induce apoptosis in cell-free systems and HeLa cells, small molecule non-peptide mimics of these peptides can be considered as a new therapeutic strategy for the treatment of diseases associated to a deficient apoptosis or resistant to the treatments with chemotherapeutic drugs. This strategy is supported by experimental evidences about the death of transformed cells and sensibilization of tumoral cells by the inhibition of the antiapoptotic proteins Bcl-2 and Bcl-xL. In the current work, these proteins complexed with X(16BH3), where X designates the proapoptotic proteins Bak, Bax, Bid and Hrk, have been modeled in order to establish a pharmacophoric hypothesis that must be present in any ligand capable of binding with the antiapoptotic proteins Bcl-2 and Bcl-xL. The pharmacophore is also used to explain the structural features of a set of new small molecule inhibitors of these antiapoptotic proteins.
authors.affiliation: Dept. de Química Física, Universitat de Barcelona, Martí i Franqués 1, E-08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pinto
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Perez
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; C484586:HRK protein, human; D008565:Membrane Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein