Discovery of novel benzophenone integrated derivatives as anti-Alzheimer's agents targeting presenilin-1 and presenilin-2 inhibition: A computational approach

The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precu...

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Bibliographic Details
Published in:PloS one 2022-04, Vol.17 (4), p.e0265022
Main Authors: Martiz, Reshma Mary, Patil, Shashank M, Ramu, Ramith, M K, Jayanthi, P, Ashwini, Ranganatha, Lakshmi V, Khanum, Shaukath Ara, Silina, Ekaterina, Stupin, Victor, Achar, Raghu Ram
Format: Article
Language:English
Subjects:
Alzheimer Disease - drug therapy
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - metabolism
Amyloid precursor protein
Amyloid Precursor Protein Secretases - metabolism
Benzophenone
Benzophenones
Binding sites
Bioinformatics
Biology and Life Sciences
Biotechnology
Computational neuroscience
Drug therapy
Enzymes
Free energy
Higher education
Humans
Hydrogen bonds
Hypotheses
In vitro methods and tests
In vivo methods and tests
Inhibitors
Lead compounds
Life sciences
Medicine and Health Sciences
Metabolism
Molecular docking
Molecular Docking Simulation
Molecular dynamics
Neurodegeneration
Neurodegenerative diseases
Patient outcomes
Pharmacology
Phenols
Physical Sciences
Presenilin 1
Presenilin 2
Presenilin-1 - metabolism
Presenilin-2 - genetics
Protein turnover
Proteins
Secretase
Simulation
Testing
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Summary:The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aβ. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer's potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0265022