Dataset Information

Computational Insights Into the Inhibition Mechanism of Proanthocyanidin B2 on Tau Hexapeptide (PHF6) Oligomer.

ABSTRACT: The formation of amyloid fibrils from Tau is a key pathogenic feature of Alzheimer's disease (AD). To disturb the formation of Tau aggregates is considered as a promising therapeutic strategy for AD. Recently, a natural product proanthocyanidin B2 (PB2) was confirmed to not only inhibit Tau aggregation, but also disaggregate Tau fibrils. Herein, to explore the inhibition mechanism of PB2 against Tau fibril and to provide the useful information for drug design and discovery, all-atom molecular dynamics simulations were carried out for the ordered Tau hexapeptide PHF6 oligomer in the presence and absence of PB2. The obtained result shows that PB2 can transform PHF6 oligomer from the ordered β-sheet structure into disordered one. Moreover, the clustering analysis and binding free energy calculations identify that S3 site is the most potential binding site. At S3 site, by hydrophobic and hydrogen bond interactions, the residues V309, Y310 and K311 are essential for binding with PB2, especially K311. In a word, our study reveals the molecular mechanism of PB2 inhibiting PHF6 aggregation and it will provide some valuable information for the development of Tau aggregation inhibitors.

SUBMITTER: Li Q

PROVIDER: S-EPMC8316602 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Computational Insights Into the Inhibition Mechanism of Proanthocyanidin B2 on Tau Hexapeptide (PHF6) Oligomer.

Li Qin Q Xiong Chunmei C Liu Hongli H Ge Huizhen H Yao Xiaojun X Liu Huanxiang H

Frontiers in chemistry 20210714

The formation of amyloid fibrils from Tau is a key pathogenic feature of Alzheimer's disease (AD). To disturb the formation of Tau aggregates is considered as a promising therapeutic strategy for AD. Recently, a natural product proanthocyanidin B2 (PB2) was confirmed to not only inhibit Tau aggregation, but also disaggregate Tau fibrils. Herein, to explore the inhibition mechanism of PB2 against Tau fibril and to provide the useful information for drug design and discovery, all-atom molecular dy ...[more]

PMID: 34336783

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Project description:Matrix metalloproteinases 1 (MMP-1) energetically triggers the enzymatic proteolysis of extracellular matrix collagenase (ECM), resulting in progressive skin aging. Natural flavonoids are well known for their antioxidant properties and have been evaluated for inhibition of matrix metalloproteins in human. Recently, (-)-epicatechin and proanthocyanidin B2 were reported as essential flavanols from various natural reservoirs as potential anti-inflammatory and free radical scavengers. However, their molecular interactions and inhibitory potential against MMP-1 are not yet well studied. In this study, sequential absorption, distribution, metabolism, and excretion (ADME) profiling, quantum mechanics calculations, and molecular docking simulations by extra precision Glide protocol predicted the drug-likeness of (-)-epicatechin (-7.862 kcal/mol) and proanthocyanidin B2 (-8.145 kcal/mol) with the least reactivity and substantial binding affinity in the catalytic pocket of human MMP-1 by comparison to reference bioactive compound epigallocatechin gallate (-6.488 kcal/mol). These flavanols in docked complexes with MMP-1 were further studied by 500 ns molecular dynamics simulations that revealed substantial stability and intermolecular interactions, viz. hydrogen and ionic interactions, with essential residues, i.e., His218, Glu219, His222, and His228, in the active pocket of MMP-1. In addition, binding free energy calculations using the Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method suggested the significant role of Coulomb interactions and van der Waals forces in the stability of respective docked MMP-1-flavonol complexes by comparison to MMP-1-epigallocatechin gallate; these observations were further supported by MMP-1 inhibition assay using zymography. Altogether with computational and MMP-1-zymography results, our findings support (-)-epicatechin as a comparatively strong inhibitor of human MMP-1 with considerable drug-likeness against proanthocyanidin B2 in reference to epigallocatechin gallate.

Dataset Information

Computational Insights Into the Inhibition Mechanism of Proanthocyanidin B2 on Tau Hexapeptide (PHF6) Oligomer.

Publications

Computational Insights Into the Inhibition Mechanism of Proanthocyanidin B2 on Tau Hexapeptide (PHF6) Oligomer.

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