<i>In Silico</i>Design of BACE1 Inhibitor for Alzheimer’s Disease by Traditional Chinese Medicine

Huang, Hung-Jin; Lee, Cheng-Chun; Chen, Calvin Yu-Chian

doi:10.1155/2014/741703

Cited by 9 publications

(7 citation statements)

References 65 publications

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“…The docking analysis represented that both two compounds interacted with the second water binding site of BACE1, where lupeol showed strong hydrophobic interactions with the flap region. These results demonstrated the inhibition mechanism of lupeol and ursolic acid, which are also consistent with the previously published docking results [23,[40][41][42][43][44][45]. Subsequently, the binding free energies of two complexes have been analyzed by MM-GBSA and MM/GBVI methods, and in both cases, lupeol showed better binding energies than ursolic acid.…”

Section: Discussionsupporting

confidence: 90%

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Hosen

Rubayed

Dash

et al. 2019

CPD

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Alzheimer disease (AD) can be considered the most common age-related neurodegenerative disorder, and also, an important cause of death in elderly patients. A number of studies found the correlation of this disease pathology with BACE1 inhibitor and it is also evident that BACE1 inhibitor can function as a very potent treatment strategy in treating AD. In the present study, we aimed to prospect for novel plant-derived BACE1 inhibitors from Leea indica and to realize the structural basis of their interactions and mechanisms using combined molecular docking and molecular dynamics based approaches. An extensive library of Leea indica plant-derived molecule was compiled and computationally screened for inhibitory action against BACE1 by using virtual screening approaches. Furthermore, induced fit docking and classical molecular dynamics along with steered molecular dynamics simulations were employed to get insight the binding mechanisms. Two triterpenoids, ursolic acid and lupeol were identified through virtual screening; wherein, lupeol showed better binding free energy in MM/GBSA, MM/PBSA and MM/GBVI approaches. Furthermore classical and steered dynamics revealed the favourable hydrophobic interactions between the lupeol and the residues of flap or catalytic dyad of BACE1; however, ursolic acid showed disfavorable interactions with the BACE1. This study, therefore, unveiled the lupeol as a potent BACE1 inhibitor from a manually curated dataset of Leea indica molecules, which may provide a new dimension of designing novel BACE1 inhibitors for AD therapy.

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Section: Discussionsupporting

confidence: 90%

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Hosen

Rubayed

Dash

et al. 2019

CPD

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“…The results showed that budmunchiamine L5 is the most favorable compound for AD treatment, because it has a good absorption and blood-brain barrier (BBB) penetration rate, and is less toxic than the other two alternatives [ 49 ]. Additionally, the inhibition of β-site APP cleaving enzyme 1 (BACE1) was studied [ 50 ]. The BACE1 is thought to possibly cause AD, because it participates in an important step in the production of amyloid beta.…”

Section: Traditional Chinese Medicine (Tcm) and Network Pharmacolomentioning

confidence: 99%

“…The BACE1 is thought to possibly cause AD, because it participates in an important step in the production of amyloid beta. TCM components that could inhibit BACE1 were investigated, and the effects of these components were evaluated using a molecular dynamics simulation [ 50 ]. It was discovered that triptofordin B1 can bind to BACE1 and inhibit it effectively, and is less toxic than pyrimidine analogue, which has similar binding abilities [ 50 ].…”

Section: Traditional Chinese Medicine (Tcm) and Network Pharmacolomentioning

confidence: 99%

“…TCM components that could inhibit BACE1 were investigated, and the effects of these components were evaluated using a molecular dynamics simulation [ 50 ]. It was discovered that triptofordin B1 can bind to BACE1 and inhibit it effectively, and is less toxic than pyrimidine analogue, which has similar binding abilities [ 50 ]. The inhibitory effects of triptofordin B1 and budmunchiamine L5 on the AD network should be further investigated.…”

Section: Traditional Chinese Medicine (Tcm) and Network Pharmacolomentioning

confidence: 99%

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Network Medicine for Alzheimer’s Disease and Traditional Chinese Medicine

et al. 2018

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Alzheimer’s Disease (AD) is a neurodegenerative condition that currently has no known cure. The principles of the expanding field of network medicine (NM) have recently been applied to AD research. The main principle of NM proposes that diseases are much more complicated than one mutation in one gene, and incorporate different genes, connections between genes, and pathways that may include multiple diseases to create full scale disease networks. AD research findings as a result of the application of NM principles have suggested that functional network connectivity, myelination, myeloid cells, and genes and pathways may play an integral role in AD progression, and may be integral to the search for a cure. Different aspects of the AD pathology could be potential targets for drug therapy to slow down or stop the disease from advancing, but more research is needed to reach definitive conclusions. Additionally, the holistic approaches of network pharmacology in traditional Chinese medicine (TCM) research may be viable options for the AD treatment, and may lead to an effective cure for AD in the future.

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“…The β-site APP cleaving enzyme 1 (BACE1) is among the most significant targets for novel drugs to treat Alzheimer's disease (AD) (Huang et al, 2014 ). The thinning of lipid bilayer has been observed due to protein amyloid-Aβ (Aβ) accumulation and oxidative stress in AD.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease

Hassan

Shahzadi

Seo

et al. 2018

Front. Comput. Neurosci.

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The design of novel inhibitors to target BACE1 with reduced cytotoxicity effects is a promising approach to treat Alzheimer's disease (AD). Multiple clinical drugs and antibodies such as AZD3293 and Solanezumab are being tested to investigate their therapeutical potential against AD. The current study explores the binding pattern of AZD3293 and Solanezumab against their target proteins such as β-secretase (BACE1) and mid-region amyloid-beta (Aβ) (PDBIDs: 2ZHV & 4XXD), respectively using molecular docking and dynamic simulation (MD) approaches. The molecular docking results show that AZD3293 binds within the active region of BACE1 by forming hydrogen bonds against Asp32 and Lys107 with distances 2.95 and 2.68 Å, respectively. However, the heavy chain of Solanezumab interacts with Lys16 and Asp23 of amyloid beta having bond length 2.82, 2.78, and 3.00 Å, respectively. The dynamic cross correlations and normal mode analyses show that BACE1 depicted good residual correlated motions and fluctuations, as compared to Solanezumab. Using MD, the Root Mean Square Deviation and Fluctuation (RMSD/F) graphs show that AZD3293 residual fluctuations and RMSD value (0.2 nm) was much better compared to Solanezumab (0.7 nm). Moreover, the radius of gyration (Rg) results also depicts the significance of AZD3293 docked complex compared to Solanezumab through residual compactness. Our comparative results show that AZD3293 is a better therapeutic agent for treating AD than Solanezumab.

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In SilicoDesign of BACE1 Inhibitor for Alzheimer’s Disease by Traditional Chinese Medicine

Cited by 9 publications

References 65 publications

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Network Medicine for Alzheimer’s Disease and Traditional Chinese Medicine

Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease

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