scholarly journals Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Wei Wang ◽  
Minghui Wan ◽  
Dongjiang Liao ◽  
Guilin Peng ◽  
Xin Xu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Natural Products ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Virtual Screening ◽  
Md Simulation ◽  
Interaction Analysis ◽  
Docking Simulation ◽  
Building Blocks ◽  
Intracellular Channel

Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.

scholarly journals Drug Design of Cyclin-Dependent Kinase 2 Inhibitor for Melanoma from Traditional Chinese Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Hsin-Chieh Tang ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Cell Cycle ◽  
Molecular Dynamics ◽  
Support Vector Machine ◽  
Systems Biology ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Md Simulation ◽  
Support Vector ◽  
Cyclin Dependent Kinase ◽  
Melanoma Therapy

One has found an important cell cycle controller. This guard can decide the cell cycle toward proliferation or quiescence. Cyclin-dependent kinase 2 (CDK2) is a unique target among the CDK family in melanoma therapy. We attempted to find out TCM compounds from TCM Database@Taiwan that have the ability to inhibit the activity of CDK2 by systems biology. We selected Tetrahydropalmatine, Reserpiline, and (+)-Corydaline as the candidates by docking and screening results for further survey. We utilized support vector machine (SVM), multiple linear regression (MLR) models and Bayesian network for validation of predicted activity. By overall analysis of docking results, predicted activity, and molecular dynamics (MD) simulation, we could conclude that Tetrahydropalmatine, Reserpiline, and (+)-Corydaline had better binding affinity than the control. All of them had the ability to inhibit the activity of CDK2 and might have the opportunity to be applied in melanoma therapy.

scholarly journals In SilicoIdentification of Potent PPAR-γAgonists from Traditional Chinese Medicine: A Bioactivity Prediction, Virtual Screening, and Molecular Dynamics Study

2014 ◽  
Vol 2014 ◽  
pp. 1-19 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Molecular Dynamics ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Virtual Screening ◽  
Prediction Models ◽  
Protein Complexes ◽  
Md Simulations ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors ◽  
Key Residues

The peroxisome proliferator-activated receptors (PPARs) related to regulation of lipid metabolism, inflammation, cell proliferation, differentiation, and glucose homeostasis by controlling the related ligand-dependent transcription of networks of genes. They are used to be served as therapeutic targets against metabolic disorder, such as obesity, dyslipidemia, and diabetes; especially, PPAR-γis the most extensively investigated isoform for the treatment of dyslipidemic type 2 diabetes. In this study, we filter compounds of traditional Chinese medicine (TCM) using bioactivities predicted by three distinct prediction models before the virtual screening. For the top candidates, the molecular dynamics (MD) simulations were also utilized to investigate the stability of interactions between ligand and PPAR-γprotein. The top two TCM candidates, 5-hydroxy-L-tryptophan and abrine, have an indole ring and carboxyl group to form the H-bonds with the key residues of PPAR-γprotein, such as residues Ser289 and Lys367. The secondary amine group of abrine also stabilized an H-bond with residue Ser289. From the figures of root mean square fluctuations (RMSFs), the key residues were stabilized in protein complexes with 5-Hydroxy-L-tryptophan and abrine as control. Hence, we propose 5-hydroxy-L-tryptophan and abrine as potential lead compounds for further study in drug development process with the PPAR-γprotein.

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
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Virtual Screening ◽  
Md Simulation ◽  
Trajectory Analysis ◽  
Computational Design ◽  
Apolipoprotein E4 ◽  
Disease Therapy

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.

scholarly journals Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products

Marine Drugs ◽  
2021 ◽  
Vol 20 (1) ◽  
pp. 29
Author(s):  
Lianxiang Luo ◽  
Ai Zhong ◽  
Qu Wang ◽  
Tongyu Zheng
Keyword(s):  
Molecular Dynamics ◽  
Natural Products ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Marine Natural Products ◽  
Md Simulation ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Dynamics Simulation ◽  
Stable Conformation

Background: In the past decade, several antibodies directed against the PD-1/PD-L1 interaction have been approved. However, therapeutic antibodies also exhibit some shortcomings. Using small molecules to regulate the PD-1/PD-L1 pathway may be another way to mobilize the immune system to fight cancer. Method: 52,765 marine natural products were screened against PD-L1(PDBID: 6R3K). To identify natural compounds, a structure-based pharmacophore model was generated, following by virtual screening and molecular docking. Then, the absorption, distribution, metabolism, and excretion (ADME) test was carried out to select the most suitable compounds. Finally, molecular dynamics simulation was also performed to validate the binding property of the top compound. Results: Initially, 13 small marine molecules were screened based on the pharmacophore model. Then, two compounds were selected for further evaluation based on the molecular docking scores. After ADME and toxicity studies, molecule 51320 was selected for further verification. By molecular dynamics analysis, molecule 51320 maintains a stable conformation with the target protein, so it has the chance to become an inhibitor of PD-L1. Conclusions: Through structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET approaches, and molecular dynamics (MD) simulation, the marine natural compound 51320 can be used as a small molecule inhibitor of PD-L1.

scholarly journals Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine

Molecules ◽  
2016 ◽  
Vol 21 (9) ◽  
pp. 1259 ◽  
Author(s):  
Fang Lu ◽  
Ganggang Luo ◽  
Liansheng Qiao ◽  
Ludi Jiang ◽  
Gongyu Li ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Virtual Screening ◽  
Cyclin Dependent Kinase ◽  
Allosteric Inhibitors
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