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Molecular docking based virtual screening of natural compounds as potential BACE1 inhibitors: 3D –QSAR pharmacophore mapping and molecular dynamics analysis

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216305%3A26220%2F15%3APU114472" target="_blank" >RIV/00216305:26220/15:PU114472 - isvavai.cz</a>

  • Výsledek na webu

    <a href="http://dx.doi.org/10.1080/07391102.2015.1022603" target="_blank" >http://dx.doi.org/10.1080/07391102.2015.1022603</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1080/07391102.2015.1022603" target="_blank" >10.1080/07391102.2015.1022603</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Molecular docking based virtual screening of natural compounds as potential BACE1 inhibitors: 3D –QSAR pharmacophore mapping and molecular dynamics analysis

  • Popis výsledku v původním jazyce

    Beta-site APP cleaving enzyme1 (BACE1) catalyzes the rate determining step in the generation of A beta peptide and is widely considered as a potential therapeutic drug target for Alzheimers disease (AD). Active site of BACE1 contains catalytic aspartic (Asp) dyad and flap. Asp dyad cleaves the substrate amyloid precursor protein with the help of flap. Currently, there are no marketed drugs available against BACE1 and existing inhibitors are mostly pseudopeptide or synthetic derivatives. There is a need to search for a potent inhibitor with natural scaffold interacting with flap and Asp dyad. This study screens the natural database InterBioScreen, followed by three-dimensional (3D) QSAR pharmacophore modeling, mapping, in silicoADME T predictions to find the potential BACE1 inhibitors. Further, molecular dynamics of selected inhibitors were performed to observe the dynamic structure of protein after ligand binding. All conformations and the residues of binding region were stable but the flap adopted a closed conformation after binding with the ligand. Bond oligosaccharide interacted with the flap as well as catalytic dyad via hydrogen bond throughout the simulation. This led to stabilize the flap in closed conformation and restricted the entry of substrate. Carbohydrates have been earlier used in the treatment of AD because of their low toxicity, high efficiency, good biocompatibility, and easy permeability through the blood–brain barrier. Our finding will be helpful in identify the potential leads to design novel BACE1 inhibitors for AD therapy.

  • Název v anglickém jazyce

    Molecular docking based virtual screening of natural compounds as potential BACE1 inhibitors: 3D –QSAR pharmacophore mapping and molecular dynamics analysis

  • Popis výsledku anglicky

    Beta-site APP cleaving enzyme1 (BACE1) catalyzes the rate determining step in the generation of A beta peptide and is widely considered as a potential therapeutic drug target for Alzheimers disease (AD). Active site of BACE1 contains catalytic aspartic (Asp) dyad and flap. Asp dyad cleaves the substrate amyloid precursor protein with the help of flap. Currently, there are no marketed drugs available against BACE1 and existing inhibitors are mostly pseudopeptide or synthetic derivatives. There is a need to search for a potent inhibitor with natural scaffold interacting with flap and Asp dyad. This study screens the natural database InterBioScreen, followed by three-dimensional (3D) QSAR pharmacophore modeling, mapping, in silicoADME T predictions to find the potential BACE1 inhibitors. Further, molecular dynamics of selected inhibitors were performed to observe the dynamic structure of protein after ligand binding. All conformations and the residues of binding region were stable but the flap adopted a closed conformation after binding with the ligand. Bond oligosaccharide interacted with the flap as well as catalytic dyad via hydrogen bond throughout the simulation. This led to stabilize the flap in closed conformation and restricted the entry of substrate. Carbohydrates have been earlier used in the treatment of AD because of their low toxicity, high efficiency, good biocompatibility, and easy permeability through the blood–brain barrier. Our finding will be helpful in identify the potential leads to design novel BACE1 inhibitors for AD therapy.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10608 - Biochemistry and molecular biology

Návaznosti výsledku

  • Projekt

  • Návaznosti

    S - Specificky vyzkum na vysokych skolach

Ostatní

  • Rok uplatnění

    2015

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS

  • ISSN

    0739-1102

  • e-ISSN

    1538-0254

  • Svazek periodika

    9

  • Číslo periodika v rámci svazku

    4

  • Stát vydavatele periodika

    US - Spojené státy americké

  • Počet stran výsledku

    11

  • Strana od-do

    1-11

  • Kód UT WoS článku

    000368702300002

  • EID výsledku v databázi Scopus

    2-s2.0-84955674383