title: Screening efficient BH3-mimetics to hBcl-B by means of peptidodynmimetic method.
abstract: The crucial residues of hBaxBH3 peptide for interaction with hBcl-B, an anti-apoptotic protein, were identified using molecular docking studies on the polypeptides and temperature-specific molecular dynamic simulations performed for the protein-peptide complex at near-physiological conditions (pH 7.0, 1 atmospheric pressure and 0.1 M NaCl). The data from the methods were examined by a 'strong residue contacts' filter strategy and the data analyses of the former and latter methods identified 10 (Q52, K57, S60, L63, K64, R65, G67, D68, D71 & S72) and 3 (S60, E61 & K64) crucial residues of the hBaxBH3 peptide for interacting with the protein, respectively. We have herein demonstrated that BH3-chemical mimetics screened using the pharmacophoric residues of hBaxBH3 obtained from the 'peptidodynmimetic method' were superior in terms of ligand efficiencies, bioavailability and pharmacokinetic properties vis-à-vis that of small molecule BH3-mimetics retrieved using the conventional 'peptidomimetic method'. The unique advantages of the 'peptidodynmimetic method' to identify efficient BH3-mimetics for modulating interfaces (composed of a large number of amino acids) of other anti-apoptotic proteins-BH3-only peptides have also been discussed in detail.
authors: Structural Biology Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur-613 401, TN, India. sivaram@scbt.sastra.edu
authors: Dakshinamurthy
authors: D
authors: Sivakumar
authors: Biswajit
authors: B
authors: Gorai
authors: Thirunavukkarasu
authors: T
authors: Sivaraman
mesh_terms: D000595:Amino Acid Sequence; D032701:Biomimetics / Q000379:methods; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000235:genetics
chemical_list: C117144:BCL2-like 10 protein; C474007:Bax protein (53-86); D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2