title: Para-(benzoyl)-phenylalanine as a potential inhibitor against LpxC of Leptospira spp.: homology modeling, docking, and molecular dynamics study.
abstract: Leptospira interrogans, a Gram-negative bacterial pathogen is the main cause of human leptospirosis. Lipid A is a highly immunoreactive endotoxic center of lipopolysaccharide (LPS) that anchors LPS into the outer membrane of Leptospira. Discovery of compounds inhibiting lipid-A biosynthetic pathway would be promising for dissolving the structural integrity of membrane leading to cell lysis and death of Leptospira. LpxC, a unique enzyme of lipid-A biosynthetic pathway was identified as common drug target of Leptospira. Herein, homology modeling, docking, and molecular dynamics (MD) simulations were employed to discover potential inhibitors of LpxC. A reliable tertiary structure of LpxC in complex with inhibitor BB-78485 was constructed in Modeller 9v8. A data-set of BB-78485 structural analogs were docked with LpxC in Maestro v9.2 virtual screening workflow, which implements three stage Glide docking protocol. Twelve lead molecules with better XP Gscore compared to BB-78485 were proposed as potential inhibitors of LpxC. Para-(benzoyl)-phenylalanine - that showed lowest XP Gscore (-10.35 kcal/mol) - was predicted to have best binding affinity towards LpxC. MD simulations were performed for LpxC and para-(benzoyl)-phenylalanine docking complex in Desmond v3.0. Trajectory analysis showed the docking complex and inter-molecular interactions was stable throughout the entire production part of MD simulations. The results indicate para-(benzoyl)-phenylalanine as a potent drug molecule against leptospirosis. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:10.
authors: a Department of Bioinformatics , SVIMS Bioinformatics Centre, SVIMS University , Tirupati , 517507 , AP , India .
authors: Dibyabhaba
authors: D
authors: Pradhan
authors: Vani
authors: V
authors: Priyadarshini
authors: Manne
authors: M
authors: Munikumar
authors: Sandeep
authors: S
authors: Swargam
authors: Amineni
authors: A
authors: Umamaheswari
authors: Aparna
authors: A
authors: Bitla
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007921:Leptospira interrogans / Q000187:drug effects* / Q000201:enzymology; D007922:Leptospirosis / Q000188:drug therapy*; D008050:Lipid A / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000096:biosynthesis; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016415:Sequence Alignment; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C466661:BB-78485; D004791:Enzyme Inhibitors; D008050:Lipid A; D008070:Lipopolysaccharides; D009281:Naphthalenes; D013449:Sulfonamides; D010649:Phenylalanine; C053764:benzoylphenylalanine; D000581:Amidohydrolases; C023079:N-acetylglucosamine deacetylase