Detail publikace

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

KUMAR, A. ROY, S. TRIPATHI, S. SHARMA, A.

Originální název

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

Český název

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

Anglický název

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

Typ

článek v časopise

Jazyk

en

Originální abstrakt

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.

Český abstrakt

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.

Anglický abstrakt

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.

Klíčová slova

Alzheimers disease, beta-secretase, virtual screening, oligosaccharide, 3D QSAR pharmacophore modeling, molecular dynamics, Asp Dyad, flap

Rok RIV

2015

Vydáno

01.04.2015

Nakladatel

Taylor and Francis

Místo

New York

Strany od

1

Strany do

11

Strany počet

11

BibTex


@article{BUT115004,
  author="Akhil {Kumar} and Sudeep {Roy} and Shubhandra {Tripathi} and Ashok {Sharma}",
  title="Molecular docking based virtual screening of natural compounds as potential BACE1 inhibitors: 3D –QSAR pharmacophore mapping and molecular dynamics analysis",
  annote="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.",
  address="Taylor and Francis",
  chapter="115004",
  doi="10.1080/07391102.2015.1022603",
  howpublished="online",
  institution="Taylor and Francis",
  number="4",
  volume="9",
  year="2015",
  month="april",
  pages="1--11",
  publisher="Taylor and Francis",
  type="journal article"
}