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.