scholarly journals Computational Design of Apolipoprotein E4 Inhibitors for Alzheimer’s Disease Therapy from Traditional Chinese Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Hung-Jin Huang ◽  
Hsin-Yi Chen ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen

Apolipoprotein E4 (Apo E4) is the major genetic risk factor in the causation of Alzheimer’s disease (AD). In this study we utilize virtual screening of the world’s largest traditional Chinese medicine (TCM) database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD) simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB) penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors.

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Hung-Jin Huang ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen

Deficiency or loss of function of Retinoblastoma-associated proteins (RbAp48) is related with Alzheimer’s disease (AD), and AD disease is associated with age-related memory loss. During normal function, RbAp48 forms a complex with the peptide FOG-1 (friend of GATA-1) and has a role in gene transcription, but an unstable complex may affect the function of RbAp48. This study utilizes the world’s largest traditional Chinese medicine (TCM) database and virtual screening to provide potential compounds for RbAp48 binding. A molecular dynamics (MD) simulation was employed to understand the variations after protein-ligand interaction. FOG1 was found to exhibit low stability after RbAp48 binding; the peptide displayed significant movement from the initial docking position, a phenomenon which matched the docking results. The protein structure of the other TCM candidates was not variable during MD simulation and had a greater stable affinity for RbAp48 binding than FOG1. Our results reveal that the protein structure does not affect ligand binding, and the top three TCM candidates Bittersweet alkaloid II, Eicosandioic acid, and Perivine might resolve the instability of the RbAp48-FOG1 complex and thus be used in AD therapy.


2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Hung-Jin Huang ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen

Theβ-site APP cleaving enzyme 1 (BACE1) is an important target for causing Alzheimer’s disease (AD), due to the brain deposition peptide amyloid beta (Aβ) require cleavages of amyloid precursor protein (APP) by BACE1 andγ-secretase, but treatments of AD still have side effect in recent therapy. This study utilizes the world largest traditional Chinese medicine (TCM) database and database screening to provide potential BACE1 inhibited compound. Molecular dynamics (MD) simulation was carried out to observe the dynamics structure after ligand binding. We found that Triptofordin B1 has less toxicity than pyrimidine analogue, which has more potent binding affinity with BACE1. For trajectory analysis, all conformations are tending to be stable during 5000 ps simulation time. In dynamic protein validation, the residues of binding region are still stable after MD simulation. For snapshot comparison, we found that Triptofordin B1 could reduce the binding cavity; the results reveal that Triptofordin B1 could bind to BACE1 and better than control, which could be used as potential lead drug to design novel BACE1 inhibitor for AD therapy.


2017 ◽  
Vol 45 (07) ◽  
pp. 1327-1344 ◽  
Author(s):  
Simin Zhou ◽  
Lanlan Dong ◽  
Yuan He ◽  
Hong Xiao

Alzheimer’s disease (AD) is associated with the unprecedented aging tendency in our world population and has become a significant health issue. The use of Traditional Chinese Medicine to treat AD has been increasing in recent years. The objective of this meta-analysis is to evaluate the effectiveness of combining acupuncture with herbal medicine to treat AD. Randomized controlled trials (RCTs) of acupuncture plus herbals versus treatment with western drugs for AD were retrieved from 11 databases. The data were extracted by two authors; dichotomous data were expressed as odds ratio (ORs) and 95% confidence intervals (CIs), while continuous data were calculated by mean differences (MDs) with 95% CIs. Although the combined analysis of the score of Activity of Daily Life (ADL) scale MD was [Formula: see text]3.59 (95% CI [Formula: see text]7.18–0.01, [Formula: see text]), which indicates there was no statistically significant difference between the two treatments at reducing the ADL scale score, the pooled results of 12 trials indicated that acupuncture plus Chinese herbal medicine was better than western drugs at improving the effectiveness rate (OR 2.24, 95% CI 1.40–3.56), the combined evidence of 11 articles showed that acupuncture plus Chinese herbal medicine was more effective than western drugs at improving the scores for the Mini Mental State Examination (MMSE) scale (2.10, 95% CI 0.69–3.51, [Formula: see text]) and the traditional Chinese medicine symptom (MD 5.07, 95% CI 3.90–6.25, [Formula: see text]). From the current research results, acupuncture plus herbal medicine may have advantages over western drugs for treating AD. Nevertheless, well-designed RCTs with a larger sample size are required in the future.


2008 ◽  
Vol 175 (1-3) ◽  
pp. 352-354 ◽  
Author(s):  
H.Q. Lin ◽  
Michelle T. Ho ◽  
Lesley S. Lau ◽  
Kelvin K. Wong ◽  
P.C. Shaw ◽  
...  

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