10 research outputs found
IDENTIFICATION OF NOVEL INHIBITORS FOR MITOGEN-ACTIVATED PROTEIN KINASE KINASE 4 BY VIRTUAL SCREENING AND MOLECULAR DYNAMICS SIMULATION TECHNIQUES
Get PDFObjective: The objective of this study was to discover a therapeutic natural lead compound against mitogen-activated protein kinase kinase 4 (MKK4) employing in silico studies.Methods: In the present study, natural compounds database was first screened for potent inhibitory activity by employing a high throughput virtual screening and molecular docking. The molecular dynamic simulation was used to analyze the stability of ligands.Results: Top ten hit compounds obtained from virtual screening and molecular docking were analyzed for their binding poses. Molecular docking studies reveal that all ten compounds bind into the same binding pocket. Molecular dynamic simulation of ZINC06091752-MKK4 and ZINC00391412-MKK4 complexes revealed stable and potential binding mode of MKK4 to ZINC06091752 and ZINC00391412.Conclusion: The potential binding mode of MKK4 to ZINC06091752 and ZINC00391412 was explored through molecular dynamic simulations. ZINC06091752 and ZINC00391412 have been identified as potential inhibitors of MKK4. Analysis of ligand efficiency profiles through assays would add more value to the current findings and may be beneficial in prostate cancer therapy.Keywords: Molecular Dynamics Simulation, Virtual Screening, Molecular Docking, Prostate Cancer, ERK Kinase-1, MKK
Peptide Design Using \alpha , \beta - Dehydro Amino Acids: From \beta -Turns to Helical Hairpins
No full textIncorporation of \alpha,\beta -dehydrophenylalanine (\bigtriangleup Phe) residue in peptides induces folded conformations: \beta -turns in short peptides and -helices in larger ones. A few exceptions - namely, \alpha -helix or flat \beta -bend ribbon structures - have also been reported in a few cases. The most favorable conformation of \bigtriangleup Phe residues are (\phi,\psi) \sim or their enantiomers. \bigtriangleup Phe is an achiral and planar residue. These features have been exploited in designing \bigtriangleup Phe zippers and helix-turn-helix motifs. \bigtriangleup Phe can be incorporated in both right and left-handed helices. In fact, consecutive occurrence of three or more \bigtriangleup Phe amino acids induce left-handed screw sense in peptides containing L-amino acids. Weak interactions involving the \bigtriangleup Phe residue play an important role in molecular association. The C-H...O=C hydrogen bond between the \bigtriangleup Phe side-chain and backbone carboxyl moiety, \pi - \pi stacking interactions between \bigtriangleup Phe side chains belonging to enantiomeric helices have shown to stabilize folding. The unusual capability of a \bigtriangleup Phe ring to form the hub of multicentered interactions namely, a donor in aromatic C-H...\pi and C-H...O=C and an acceptor in a interaction suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures
Peptide design using α,β-dehydro amino acids: from β-turns to helical hairpins
No full textIncorporation of α,β-dehydrophenylalanine (ΔPhe) residue in peptides induces folded conformations: β-turns in short peptides and 3<SUB>10</SUB>-helices in larger ones. A few exceptions-namely, α-helix or flat β-bend ribbon structures-have also been reported in a few cases. The most favorable conformation of ΔPhe residues are (Φ,ψ) ~ (−60°, −30°), (−60°, 150°), (80°, 0°) or their enantiomers. ΔPhe is an achiral and planar residue. These features have been exploited in designing ΔPhe zippers and helix-turn-helix motifs. ΔPhe can be incorporated in both right and left-handed helices. In fact, consecutive occurrence of three or more ΔPhe amino acids induce left-handed screw sense in peptides containing L-amino acids. Weak interactions involving the ΔPhe residue play an important role in molecular association. The C-H<SUP>...</SUP>O=C hydrogen bond between the ΔPhe side-chain and backbone carboxyl moiety, π-π stacking interactions between ΔPhe side chains belonging to enantiomeric helices have shown to stabilize folding. The unusual capability of a ΔPhe ring to form the hub of multicentered interactions namely, a donor in aromatic C-H<SUP>...</SUP>π and C-H<SUP>...</SUP>O=C and an acceptor in a CH<SUB>3</SUB><SUP>...</SUP>π interaction suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures
α,α-Dehydrophenylalanine containing cecropin-melittin hybrid peptides: conformation and activity
No full textSynthesis and conformational studies of a cecropin-melittin hybrid pentadecapeptide CA(1-7)MEL(2-9), and its three α, β-dehydrophenylalanine (ΔPhe) containing analogs in water-TFE mixtures are described. ΔPhe is placed at strategic positions in order to preserve the amphipathicity of the molecule. The wild type CAMEL0 and its three analogs, containing one, two and three ΔPhe residues namely CAMELΔPhe1, CAMELΔPhe2 and CAMELΔPhe3 respectively were synthesized in solid phase and their conformation determined by CD and NMR. CAMELΔPhe2 and CAMELΔPhe3 peptides exhibit the presence of 3<SUB>10</SUB>-helix and β-turns in the former and only turns in the latter. CAMELΔPhe1 peptide was found to have a largely extended conformation. Antibacterial and hemolytic activities of the peptides were also evaluated. CAMELΔPhe2 peptide is maximally potent against both Staphylococcus aureus ATCC 259230 and Escherichia coli ATCC 11303. CAMELΔPhe1 with a single ?Phe at the center shows minimal hemolysis
Human caveolin-1 a potent inhibitor for prostate cancer therapy: a computational approach
No full textDehydrophenylalanine zippers: strong helix–helix clamping through a network of weak interactions
No full textDehydrophenylalanine zippers: strong helix-helix clamping through a network of weak interactions
No full textA decapeptide Boc-L-Ala-(ΔPhe)4-L-Ala-(ΔPhe)3-Gly-OMe (Peptide I) was synthesized to study the preferred screw sense of consecutive α,β-dehydrophenylalanine (ΔPhe) residues. Crystallographic and CD studies suggest that, despite the presence of two L-Ala residues in the sequence, the decapeptide does not have a preferred screw sense. The peptide crystallizes with two conformers per asymmetric unit, one of them a slightly distorted right-handed 310-helix (X) and the other a left-handed 310-helix (Y) with X and Y being antiparallel to each other. An unanticipated and interesting observation is that in the solid state, the two shape-complement molecules self-assemble and interact with an extensive network of C-H···O hydrogen bonds and π-π interactions, directed laterally to the helix axis with amazing regularity. Here, we present an atomic resolution picture of the weak interaction mediated mutual recognition of two secondary structural elements and its possible implication in understanding the specific folding of the hydrophobic core of globular proteins and exploitation in future work on de novo design
Role of a two-residue spacer in an α,β-didehydrophenylalanine containing hexapeptide: crystal and solution structure of Boc-Val-ΔPhe-Leu-Ala-ΔPhe-Ala-OMe
No full textThe peptide Boc-Val<SUP>1</SUP>-ΔPhe<SUP>2</SUP>-Leu<SUP>3</SUP>-Ala<SUP>4</SUP>-ΔPhe<SUP>5</SUP>-Ala<SUP>6</SUP>-OMe has been examined for the structural consequence of placing a two-residue segment between the ΔPhe residues. The peptide is stabilized by four consecutive β-turns. The overall conformation of the molecule is a right-handed 3<SUB>10</SUB>-helix, with average (Φ, ψ) values (−67.7°, −22.7°), unwound at the C-terminus. The <SUP>1</SUP>H NMR results also suggest that the peptide maintains its 3<SUB>10</SUB>-helical structure in solution as observed in the crystal state. The crystal structure is stabilized through head-to-tail hydrogen bonds and a repertoire of aromatic interactions laterally directed between adjacent helices, which are antiparallel to each other. The aromatic ring of ΔPhe<SUP>5</SUP> forms the hub of multicentred interactions, namely as a donor in aromatic C-H<SUP>...</SUP>π and aromatic C-H<SUP>...</SUP>O-C interactions and as an acceptor in a CH<SUB>3</SUB><SUP>...</SUP>π interaction. The present structure uniquely illustrates the unusual capability of a ΔPhe ring to host such concerted interactions and suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures
Self-assembly of a dipeptide-containing conformationally restricted dehydrophenylalanine residue to form ordered nanotubes
No full textThe self-assembly of a dehydrophenylalanine containing dipeptide (see figure), yielding highly ordered nanotubular structures, is discussed. The tubes are longer and thinner than previously reported peptide-based tubular structures; they are stable to boiling-water temperatures, different pH conditions, and to a highly nonspecific protease (Proteinase K)
