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Novel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations.

ABSTRACT: A major genetic suspect for Alzheimer's disease is the pathological conformation assumed by apolipoprotein E4 (ApoE4) through intramolecular interaction. In the present study, a large library of natural compounds was screened against ApoE4 to identify novel therapeutic molecules that can prevent ApoE4 from being converted to its pathological conformation. We report two such natural compounds PHC and IAH that bound to the active site of ApoE4 during the docking process. The binding analysis suggested that they have a strong mechanistic ability to correct the pathological structural orientation of ApoE4 by preventing repulsion between Arg 61 and Arg 112, thus inhibiting the formation of a salt bridge between Arg 61 and Glu 255. However, when the molecular dynamics simulations were carried out, structural changes in the PHC-bound complex forced PHC to move out of the cavity thus destabilizing the complex. However, IAH was structurally stable inside the binding pocket throughout the simulations trajectory. Our simulations results indicate that the initial receptor-ligand interaction observed after docking could be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favored and should be better representations of derivative poses in the receptor.

SUBMITTER: Goyal M

PROVIDER: S-EPMC3845489 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Novel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations.

Goyal Manisha M Grover Sonam S Dhanjal Jaspreet Kaur JK Goyal Sukriti S Tyagi Chetna C Chacko Sajeev S Grover Abhinav A

BioMed research international 20131113

A major genetic suspect for Alzheimer's disease is the pathological conformation assumed by apolipoprotein E4 (ApoE4) through intramolecular interaction. In the present study, a large library of natural compounds was screened against ApoE4 to identify novel therapeutic molecules that can prevent ApoE4 from being converted to its pathological conformation. We report two such natural compounds PHC and IAH that bound to the active site of ApoE4 during the docking process. The binding analysis sugge ...[more]

PMID: 24324968

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Project description:Illicit drugs are a global health problem, since both their acute and chronic consumption have negative impacts on the drug user's health. Drug checking facilities are receiving growing interest as they allow drug users to chemically analyze their product prior to consumption to assess the presence of adulterants or other non-expected substances. Such harm reduction programs allow the reduction of the risks associated with drug consumption without encouraging it. In particular, the emergence of new psychoactive substances (NPS) emphasizes the risk for the population increasing the diversity and the lability of illicit drugs on the market. Analytical developments are required to catch up with this rapid evolution and reduce the potential harm caused by such consumption. In this study, we developed a matrix-assisted laser desorption/ionization (MALDI) high-resolution mass spectrometry (HRMS) strategy for the high-throughput qualitative and quantitative analysis of drug checking samples. The use of online-based m/z cloud library for untargeted compound search improved the ability to identify unknown compounds. Sixty-seven drug checking samples were analyzed using this analytical strategy, allowing the detection of 10 designer drugs and several classical drugs of abuse (mainly cocaine and MDMA) as well as adulterants and contaminants. The results were then compared with routine analyses of the same samples using conventional approaches showing similar performance while removing the use of chromatographic separation thus resulting in a significant reduction of the time required for sample preparation and analysis. This study enlightens the potential of MALDI-HRMS as a high-throughput approach allowing to speed-up up to six times the identification and quantification of substances enabling to catch the fast changes on the drug of abuse market. This strategy could be an interesting alternative analytical approach, allowing better prevention and harm reduction for drug users.

Dataset Information

Novel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations.

Publications

Novel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations.

Similar Datasets

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