Deep Learning and Random Forest Approach for Finding the Optimal Traditional Chinese Medicine Formula for Treatment of Alzheimer's Disease.

It has demonstrated that glycogen synthase kinase 3ß (GSK3ß) is related to Alzheimer's disease (AD). On the basis of the world largest traditional Chinese medicine (TCM) database, a network-pharmacology-based approach was utilized to investigate TCM candidates that can dock well with multiple targets. Support vector machine (SVM) and multiple linear regression (MLR) methods were utilized to obtain predicted models. In particular, the deep learning method and the random forest (RF) algorithm were adopted. We achieved R2 values of 0.927 on the training set and 0.862 on the test set with deep learning and 0.869 on the training set and 0.890 on the test set with RF. Besides, comparative molecular similarity indices analysis (CoMSIA) was performed to get a predicted model. All of the training models achieved good results on the test set. The stability of GSK3ß protein-ligand complexes was evaluated using 100 ns of MD simulation. Methyl 3- O-feruloylquinate and cynanogenin A induced both more compactness to the GSK3ß complex and stable conditions at all simulation times, and the GSK3ß complex also had no substantial fluctuations after a simulation time of 5 ns. For TCM molecules, we used the trained models to calculate predicted bioactivity values, and the optimum TCM candidates were obtained by ranking the predicted values. The results showed that methyl 3- O-feruloylquinate contained in Phellodendron amurense and cynanogenin A contained in Cynanchum atratum are capable of forming stable interactions with GSK3ß.

Network pharmacology-based approach of novel traditional Chinese medicine formula for treatment of acute skin inflammation in silico.

Matrix metalloproteinase-9 (MMP-9) appears to play an important role in acute skin inflammation. Subantimicrobial dose of tetracycline has been demonstrated to inhibit the activity of MMP-9 protein. However, long-term use tetracycline will induce side effect. The catalytic site of MMP-9 is located at zinc-binding amino acids, His401, His405 and His411. We attempted to search novel medicine formula as MMP-9 inhibitors from traditional Chinese medicine (TCM) database by using in silico studies. We utilized high-throughput virtual screening to find which natural compounds could bind to the zinc-binding site. The quantitative structure-activity relationship (QSAR) models, which constructed by scaffold of MMP-9 inhibitors and its activities, were employed to predict the bio-activity of the natural compounds for MMP-9. The results showed that Celacinnine, Lobelanidine and Celallocinnine were qualified to interact with zinc-binding site and displayed well predictive activity. We found that celallocinnine was the best TCM compound for zinc binging sites of MMP-9 because the stable interactions were observed under dynamic condition. In addition, Celacinnine and Lobelanidine could interact with MMP-9 related protein that identified by drug-target interaction network analysis. Thus, we suggested the herbs Hypericum patulum, Sedum acre, and Tripterygium wilfordii that containing Celallocinnine, Celacinnine and Lobelanidine might be a novel medicine formula to avoid the side effect of tetracycline and increase the efficacy of treatment.

Susceptible gene of stasis-stagnation constitution from genome-wide association study related to cardiovascular disturbance and possible regulated traditional Chinese medicine.

BACKGROUND: This study identified susceptible loci related to the Yu-Zhi (YZ) constitution, which indicates stasis-stagnation, found in a genome-wide association study (GWAS) in patients with type 2 diabetes and possible regulated traditional Chinese medicine (TCM) using docking and molecular dynamics (MD) simulation. METHODS: Non-aboriginal Taiwanese with type 2 diabetes were recruited. Components of the YZ constitution were assessed by a self-reported questionnaire. Genome-wide SNP genotypes were obtained using the Illumina HumanHap550 platform. The world's largest TCM database ( http://tcm.cmu.edu.tw/ ) was employed to investigate potential compounds for PON2 interactions. RESULTS: The study involved 1,021 unrelated individuals with type 2 diabetes. Genotyping data were obtained from 947 of the 1,021 participants. The GWAS identified 22 susceptible single nucleotide polymorphisms on 13 regions of 11 chromosomes for the YZ constitution. Genotypic distribution showed that PON2 on chromosome 7 was most significantly associated with the risk of the YZ constitution. Docking and MD simulation indicated 13-hydroxy-(9E_11E)-octadecadienoic acid was the most stable TCM ligand. CONCLUSIONS: Risk loci occurred in PON2, which has antioxidant properties that might protect against atherosclerosis and hyperglycemia, showing it is a susceptible gene for the YZ constitution and possible regulation by 13-hydroxy-(9E_11E)-octadecadienoic acid.

Treatment of acute lymphoblastic leukemia from traditional chinese medicine.

Acute lymphoblastic leukemia (ALL) is a cancer that immature white blood cells continuously overproduce in the bone marrow. These cells crowd out normal cells in the bone marrow bringing damage and death. Methotrexate (MTX) is a drug used in the treatment of various cancer and autoimmune diseases. In particular, for the treatment of childhood acute lymphoblastic leukemia, it had significant effect. MTX competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis so as to inhibit purine synthesis. In addition, its downstream metabolite methotrexate polyglutamates (MTX-PGs) inhibit the thymidylate synthase (TS). Therefore, MTX can inhibit the synthesis of DNA. However, MTX has cytotoxicity and neurotoxin may cause multiple organ injury and is potentially lethal. Thus, the lower toxicity drugs are necessary to be developed. Recently, diseases treatments with Traditional Chinese Medicine (TCM) as complements are getting more and more attention. In this study, we attempted to discover the compounds with drug-like potential for ALL treatment from the components in TCM. We applied virtual screen and QSAR models based on structure-based and ligand-based studies to identify the potential TCM component compounds. Our results show that the TCM compounds adenosine triphosphate, manninotriose, raffinose, and stachyose could have potential to improve the side effects of MTX for ALL treatment.

Lead discovery for Alzheimer's disease related target protein RbAp48 from traditional Chinese medicine.

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.

Possible inhibitor from traditional Chinese medicine for the ß form of calcium-dependent protein kinase type II in the treatment of major depressive disorder.

Recently, an important topic of major depressive disorder (MDD) had been published in 2013. MDD is one of the most prevalent and disabling mental disorders. Consequently, much research is being undertaken into the causes and treatment. It has been found that inhibition of the ß form of calcium/calmodulin-dependent protein kinase type II (ß-CaMKII) can ameliorate the disorder. Upon screening the traditional Chinese medicine (TCM) database by molecular docking, sengesterone, labiatic acid, and methyl 3-O-feruloylquinate were selected for molecular dynamics. After 20 ns simulation, the RMSD, total energy, and structure variation could define the protein-ligand interaction. Furthermore, sengesterone, the principle candidate compound, has been found to have an effect on the regulation of emotions and memory development. In structure variation, we find the sample functional group of important amino acids make the protein stable and have limited variation. Due to similarity of structure variations, we suggest that these compounds may have an effect on ß-CaMKII and that sengesterone may have a similar efficacy as the control. However labiatic acid may be a stronger inhibitor of ß-CaMKII based on the larger RMSD and variation.

Lead Screening for Chronic Obstructive Pulmonary Disease of IKK2 Inhibited by Traditional Chinese Medicine.

Chronic obstructive pulmonary disease (COPD) is a chronic obstructive lung disease and is frequently found in well-developed countries due to the issue of aging populations. Not all forms of medical treatment are unable to return a patient's limited pulmonary function back to normal and eventually they could require a lung transplant. At this time, COPD is the leading cause of death in the world. Studies surveying I-kappa-B-kinase beta (IKK2) are very relevant to the occurrence and deterioration of the condition COPD. The sinapic acid-4-O-sulfate, kaempferol, and alpha-terpineol were found to be IKK2 inhibitors and helped prevent COPD occurrence and worsening according to a screening of the traditional Chinese medicine (TCM) database. The protein-ligand interaction of these three compounds with regard to IKK2 was also done by molecular dynamics. The docking poses, hydrogen bond variation, and hydrophobic interactions found Asp103 and Lys106 are crucial to IKK2 binding areas for IKK2 inhibition. Finally, we found the three compounds that have an equally strong effect in terms of IKK2 binding proven by the TCM database and perhaps these may be an alternative treatment for COPD in the future.

Computational design of apolipoprotein E4 inhibitors for Alzheimer's disease therapy from traditional Chinese medicine.

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.

In silico design of BACE1 inhibitor for Alzheimer's disease by traditional Chinese medicine.

The ß-site APP cleaving enzyme 1 (BACE1) is an important target for causing Alzheimer's disease (AD), due to the brain deposition peptide amyloid beta (Aß) require cleavages of amyloid precursor protein (APP) by BACE1 and γ-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.

Finding inhibitors of mutant superoxide dismutase-1 for amyotrophic lateral sclerosis therapy from traditional chinese medicine.

Superoxide dismutase type 1 (SOD1) mutations cause protein aggregation and decrease protein stability, which are linked to amyotrophic lateral sclerosis (ALS) disease. This research utilizes the world's largest traditional Chinese medicine (TCM) database to search novel inhibitors of mutant SOD1, and molecular dynamics (MD) simulations were used to analyze the stability of protein that interacted with docked ligands. Docking results show that hesperidin and 2,3,5,4'-tetrahydroxystilbene-2-O- ß -D-glucoside (THSG) have high affinity to mutant SOD1 and then dopamine. For MD simulation analysis, hesperidin and THSG displayed similar value of RMSD with dopamine, and the migration analysis reveals stable fluctuation at the end of MD simulation time. Interestingly, distance between the protein and ligand has distinct difference, and hesperidin changes the position from initial binding site to the other place. In flexibility of residues analysis, the secondary structure among all complexes does not change, indicating that the structure are not affect ligand binding. The binding poses of hesperidin and THSG are similar to dopamine after molecular simulation. Our result indicated that hesperidin and THSG might be potential lead compound to design inhibitors of mutant SOD1 for ALS therapy.

Lead Screening for HIV of C-C Chemokine Receptor Type 5 Receptor Inhibited by Traditional Chinese Medicine.

The acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), has become a serious world-wide problem because of this disease's rapid propagation and incurability. Recent research has pointed out that the C-C chemokine receptor type 5 (CCR5) is an important target for HIV infection. The traditional Chinese medicine (TCM) database (http://tcm.cmu.edu.tw/) has been screened for molecular compounds that, by simulating molecular docking and molecular dynamics, may protect CCR5 against HIV. Saussureamine C, 5-hydroxy-L-tryptophan, and abrine are selected based on the docking score being higher than Maraviroc and other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. According to the docking poses, hydrophobic interactions, and hydrogen bond variations, this research surmises TRP86, TYR108, GLN194, TYR251, and GLU283 are the main regions of important amino acids in CCR5. In addition to the detection of TCM compound efficacy, we suggest saussureamine C is better than the others for maintaining protein composition during protein-ligand interaction, based on the structural variation.

Investigation of anti-infection mechanism of lactoferricin and splunc-1.

The innate immune system is the first line in the defense system and prevents the body from further bacteria, virus, or fungal infections. Most of the innate immune system is relevant to mucosa immunity. Lactotransferrin is secreted from the human mammal breast duct epithelial tissue and strengthens infant immunity to defense with regard to outward pathogens. Splunc-1 is also an innate material secreted from the soft palate, lung, nasal cavity epithelium, and mucosa. It helps with mucosa defense against bacterial, virus, and even fungus. LPS is the main etiology of Gram-negative bacilla infection source. And studies of lactoferricin and slpunc-1 both can combine with LPS and subsequently cause insults to the mucosa. Although, we know that both of them partake in an important role in innate immunity, we do not know the effects when they work together. In this study, we just overview silicon stimulation to examine the combination of Lactoferricin and Splunc-1 and the effect with regard to LPS.

Pharmacological chaperone design for reducing risk factor of Parkinson's disease from traditional chinese medicine.

Dysfunction of ß -glucocerebrosidase (GCase) has no hydrolytic activity in patients of Gaucher's disease and increasing the risk factor for Parkinson's disease occurrence. Pharmacological chaperone design has been used to treat with misfolded protein in related disease, which utilized a small compound to cause protein folding correctly. This study employed the world largest traditional Chinese medicine (TCM) database for searching for potential lead compound as pharmacological chaperone, and we also performed molecular dynamics (MD) simulations to observe the stability of binding conformation between ligands and active site of GCase structure. The docking results from database screening show that N-methylmescaline and shihunine have high binding ability to GCase than tetrahydroxyazepanes. From MD simulation analysis, tetrahydroxyazepanes displayed high opportunity of ligand migration instead of our TCM candidates, and H-bonds number was decreased in the end of MD snapshot. Our result indicated that binding conformation of N-methylmescaline and shihunine remains stable during MD simulation, demonstrating that the two candidates are suitable for GCase binding and might be potential as pharmacological chaperone for GCase folding correctly.

Traditional Chinese medicine application in HIV: an in silico study.

Viral infection by human immunodeficiency virus (HIV) requires integration of viral DNA with host DNA which involves the binding of HIV integrase (IN) with its co-factor lens epithelium-derived growth factor (LEDGF/p75). Since disrupted binding of IN with LEDGF/p75 inhibits proliferation of HIV, inhibition or denaturation of IN is a possible method for inhibiting HIV replication. D77 is a known drug with demonstrated inhibition against HIV by binding to IN. Herein, we utilized D77 as a control to screen for traditional Chinese medicine (TCM) compounds that exhibit similar atomic-level characteristics. 9-Hydroxy-(10E)-octadecenoic acid and Beauveriolide I were found to have higher Dock Scores to IN than D77 through virtual screening. Multiple linear regression (R2 = 0.9790) and support vector machine (R2 = 0.9114) models consistently predicted potential bioactivity of the TCM candidates against IN. The 40 ns molecular dynamics simulation showed that the TCM compounds fulfilled the drug-like criteria of forming stable complexes with IN. Atomic-level investigations revealed that 9-hydroxy-(10E)-octadecenoic acid bound to an important residue A:Lys173, and Beauveriolide I formed stable interactions with the core LEDGF binding site and with Asn256 of the IN binding site on LEDGF. The TCM candidates also initiated loss of α-helices that could affect the functionality of IN. Taken together, the ability of 9-hydroxy-(10E)-octadecenoic acid and Beauveriolide I to (1) form stable interactions affecting IN-LEDGF binding and (2) have predicted bioactivity against IN suggests that the TCM candidates might be potential starting structures for developing compounds that may disrupt IN-LEDGF binding. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:40.

A possible solution for hair loss by inhibiting corticotropin-releasing factor (CRF) receptor from traditional Chinese medicine.

Corticotropin-releasing factor (CRF) and corticotropin-releasing factor receptor (CRFR) play important roles in stress response, including anxiety and depression syndrome. The CRF expression also relates to chronic stress-related hair loss. This study utilizes the world's largest traditional Chinese medicine (TCM) database and molecular dynamics (MD) simulations to investigate novel CRFR inhibitors for treatment of alopecia. The docking and screening from TCM database results indicate the vitamin B2, 3 beta-isodihydrocadambine, and caribine display higher binding affinity than maltose in maltose binding protein (MBP). However, the results of MD simulation shows the caribine-facilitated CRFR approach closer to MBP, the 3D structure conformation of MBP and CRFR complex forms compact structure. Interestingly, the distance between the two proteins is reducing significantly after caribine dock into MBP binding site. Beside, from Ligand channel analysis, the paths of caribine demonstrate that residence time is increased in binding pocket. Hence, our finding suggests that caribine might be a potential lead compound to stimulate MBP and CRFR interaction, and help for baldless therapy in further study.

Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine.

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.

High performance screening, structural and molecular dynamics analysis to identify H1 inhibitors from TCM Database@Taiwan.

New-type oseltamivir-resistant H1N1 influenza viruses have been a major threat to human health since the 2009 flu pandemic. To resolve the drug resistance issue, we aimed to identify a new type of inhibitors against H1 from traditional Chinese medicine (TCM) by employing the world's largest TCM database () for virtual screening and molecular dynamics (MD). From the virtual screening results, sodium (+)-isolaricireinol-2 alpha-sulfate, sodium 3,4-dihydroxy-5-methoxybenzoic acid methyl ester-4-sulfate, sodium (E)-7-hydroxy-1,7-bis(4-hydroxyphenyl)hept-5-ene-3S-sulfonate, and 3-methoxytyramine-betaxanthin were identified as potential drug-like compounds. MD simulation of the binding poses with the key residues Asp103 and Glu83, as well as other binding site residues, identified higher numbers of hydrogen bonds than N-Acetyl-D-Glucosamine (NAG), the natural ligand of the esterase domain in H1. Ionic bonds, salt bridges, and electrostatic energy also contribute to binding stability. Key binding residues include Lys71, Glu83, Asp103, and Arg238. Structural moieties promoting H-bond or salt bridge formations at these locations greatly contribute to a stable ligand-protein complex. An available sodium atom for ionic interactions with Asp103 can further stabilize the ligands. Based on virtual screening, MD simulation, and interaction energy evaluation, TCM candidates demonstrate good potential as novel H1 inhibitors. In addition, the identified stabilizing features can provide insights for designing highly stable H1 inhibitors.

Blocking the DNA repair system by traditional Chinese medicine?

Non-homologous end joining (NHEJ) is a major DNA double strand breaks (DSBs) repair pathway that maintains genome integrity. However, this pathway may reduce radiotherapy efficacy by repairing DSBs on cancer cells. This research reported a computer-aided drug design (CADD) method to identify novel inhibitors from traditional Chinese medicine (TCM) that disrupt NHEJ. We aim to inhibit Ku86, the initiator of NHEJ. By integrating binding energy evaluation and molecular dynamics simulation methods, we reported glycyrrhizic acid, macedonoside C, lithospermic acid, and salvianolic acid B as potential Ku86 inhibitors. All four TCM compounds show low binding energy and stable binding poses to Ku86. The carboxyl groups on a ligand are the major binding region by forming salt bridges at Ku86 binding sites. Additional features were defined by a carbonyl group or a dihydroxyphenyl group that form additional hydrogen bond or pi-cation respectively with the ligand binding site on Ku86. These features strengthen the binding affinity between Ku86 and the potential TCM ligand. We reported all four TCM compounds are potential Ku86 inhibitors and may be used to enhance radiotherapy for cancer treatment.

Two birds with one stone? Possible dual-targeting H1N1 inhibitors from traditional Chinese medicine.

The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza.