IDENTIFICATION OF NOVEL INHIBITORS FOR MITOGEN-ACTIVATED PROTEIN KINASE KINASE 4 BY VIRTUAL SCREENING AND MOLECULAR DYNAMICS SIMULATION TECHNIQUES

Objective: 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

Incorporation of \alpha,\beta -dehydrophenylalanine (\bigtriangleup Phe) residue in peptides induces folded conformations: \beta -turns in short peptides and $3_{10}$ -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 $(-60^o, -30^o), (-60^o, 150^o), (80^o, 0^o)$ 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 $CH_3...\pi$ 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

Incorporation of &#945;,&#946;-dehydrophenylalanine (&#916;Phe) residue in peptides induces folded conformations: &#946;-turns in short peptides and 3<SUB>10</SUB>-helices in larger ones. A few exceptions-namely, &#945;-helix or flat &#946;-bend ribbon structures-have also been reported in a few cases. The most favorable conformation of &#916;Phe residues are (&#934;,&#968;) ~ (&#8722;60&#176;, &#8722;30&#176;), (&#8722;60&#176;, 150&#176;), (80&#176;, 0&#176;) or their enantiomers. &#916;Phe is an achiral and planar residue. These features have been exploited in designing &#916;Phe zippers and helix-turn-helix motifs. &#916;Phe can be incorporated in both right and left-handed helices. In fact, consecutive occurrence of three or more &#916;Phe amino acids induce left-handed screw sense in peptides containing L-amino acids. Weak interactions involving the &#916;Phe residue play an important role in molecular association. The C-H<SUP>...</SUP>O=C hydrogen bond between the &#916;Phe side-chain and backbone carboxyl moiety, &#960;-&#960; stacking interactions between &#916;Phe side chains belonging to enantiomeric helices have shown to stabilize folding. The unusual capability of a &#916;Phe ring to form the hub of multicentered interactions namely, a donor in aromatic C-H<SUP>...</SUP>&#960; and C-H<SUP>...</SUP>O=C and an acceptor in a CH<SUB>3</SUB><SUP>...</SUP>&#960; interaction suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures