Abstract
The microtubule-binding protein tau has been the center of researches concerning Alzheimer’s disease (AD) due to several clinical trials of β-amyloid therapies failing recently. The availability of the tau fibril structure from AD brain enables computational modeling studies to calculate binding affinities with different ligands. In this study, the tau paired helical filaments (PHF-Tau) (PDB ID: 5O3L) was used as receptor and interactions with the lipids: 3-alpha-cholesterol; 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; and C18:1 sphingomyelin, were explored with molecular docking, molecular dynamics, and natural bond orbital analysis. Docking sites upon solvation of the protein with transferable interatomic potential-3 points reveal the amphipathic nature of PHF-Tau and molecular dynamics simulations show that the embedded phosphocholine at the tail side gives high potential energy values with some amino acids forming H-bond interactions.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, which was discovered in 1906 that affects the aged population that until now there are no mechanism-based therapies [1]
In June 2021, the US Food and Drug Administration (FDA) has approved Aducanumab as AD treatment which is the first of its kind to treat the cause of the disease rather than the symptom [9]
This paper aims to give computationally determined structures of PHF-Tau—membrane lipid complexes and to study the interactions involved which could lead to discovery of other compounds that have effect on the protein as well and develop new drugs against AD
Summary
Alzheimer’s disease (AD) is the most common form of dementia, which was discovered in 1906 that affects the aged population that until now there are no mechanism-based therapies [1]. There are four drugs that have been approved and currently used in symptomatic treatment for AD [4]. Three of them are classified as cholinesterase inhibitors namely: donepezil [5], rivastigmine [6], and galantamine [7], and the other approved drug is based on N-methyl-D-aspartate receptor antagonist which is the memantine [8]. In June 2021, the US Food and Drug Administration (FDA) has approved Aducanumab as AD treatment which is the first of its kind to treat the cause of the disease rather than the symptom [9]. The approval by US FDA sparked some concern from the scientific community since there is not enough evidence to show that the treatment can slow cognitive decline [9]
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