Drug Repurposing of Metabolic Agents in Malignant Glioma.

Int J Mol Sci. 2018 Sep 14;19(9):

Authors: Seliger C, Hau P

Abstract
Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different specific and unspecific agents. Drug repurposing is of increasing interest in glioma research. Drugs interfering with the patient's metabolism may also influence glioma metabolism. In this review, we outline definitions and methods for drug repurposing. Furthermore, we give insights into important candidates for a metabolic drug repurposing, namely metformin, statins, non-steroidal anti-inflammatory drugs, disulfiram and lonidamine. Advantages and pitfalls of drug repurposing will finally be discussed.

PMID: 30223473 [PubMed - in process]

Repurposing of Drugs Targeting YAP-TEAD Functions.

Cancers (Basel). 2018 Sep 14;10(9):

Authors: Elisi GM, Santucci M, D'Arca D, Lauriola A, Marverti G, Losi L, Scalvini L, Bolognesi ML, Mor M, Costi MP

Abstract
Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway's terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology. Moreover, this could be relevant to obtain new molecular tools and potential therapeutic assets. In this review, we discuss the main mechanisms of action of the best-known compounds, clinically approved or investigational drugs, able to cross-talk and modulate the Hippo pathway, as an attractive strategy for the discovery of new potential lead compounds.

PMID: 30223434 [PubMed]

Recent therapeutic approaches for the management of tuberculosis: Challenges and opportunities.

Biomed Pharmacother. 2018 Mar;99:735-745

Authors: Patil K, Bagade S, Bonde S, Sharma S, Saraogi G

Abstract
Tuberculosis is a highly contagious disease spread by Mycobacterium tuberculosis. It is responsible for highest numbers of death and soon will surpass the deaths caused by HIV. The pandemic disease causes, estimated 10.4 million new infections, among which 5.9 million were men, 3.5 million were women, 1.0 million were children and the HIV patients co-infected with tuberculosis accounted for 1.2 million of all new cases in 2015, alone. The increased number of drug resistant (MDR/XDR) strains and the failure of the conventional regimens against this strain are the challenges of the coming decades. The goals of new therapeutic approaches are to ensure cure without relapse, to inhibit deaths, contagions and the formation of drug-resistant strains. The main approaches of anti-tubercular therapy involves either development of new chemical entity with a novel mechanism of action or repurposing of old drugs which show significant activity on drug-resistant strains. Repurposing existing drugs is a promising alternative to the expensive and time-consuming process of drug discovery. A number of carrier-based drug delivery systems incorporating the principal anti-tuberculosis drug has been developed to provide targeted action with reduced dosing frequency in order to improve the patient compliance which is a major reason for therapeutic treatment failure. This article reviews the recent approaches to the treatment of tuberculosis in terms of discovery of new chemical entity, repurposing of old drugs and the use of novel drug delivery technology such as liposomes, niosomes, liquid crystals, solid lipid nanoparticles, polymeric micelles, dendrimers, nanoemulsion, nanosuspension, silica nanoparticles, polymeric nanoparticles and microparticles for complete eradication of Mycobacterium tuberculosis.

PMID: 29710471 [PubMed - indexed for MEDLINE]

Drug Target Commons 2.0: a community platform for systematic analysis of drug-target interaction profiles.

Database (Oxford). 2018 Jan 01;2018:1-13

Authors: Tanoli Z, Alam Z, Vähä-Koskela M, Ravikumar B, Malyutina A, Jaiswal A, Tang J, Wennerberg K, Aittokallio T

Abstract
Drug Target Commons (DTC) is a web platform (database with user interface) for community-driven bioactivity data integration and standardization for comprehensive mapping, reuse and analysis of compound-target interaction profiles. End users can search, upload, edit, annotate and export expert-curated bioactivity data for further analysis, using an application programmable interface, database dump or tab-delimited text download options. To guide chemical biology and drug-repurposing applications, DTC version 2.0 includes updated clinical development information for the compounds and target gene-disease associations, as well as cancer-type indications for mutant protein targets, which are critical for precision oncology developments.

PMID: 30219839 [PubMed - in process]

Insights into respiratory disease through bioinformatics.

Respirology. 2018 Sep 14;:

Authors: Hurgobin B, de Jong E, Bosco A

Abstract
Respiratory diseases such as asthma, chronic obstructive pulmonary disease and lung cancer represent a critical area for medical research as millions of people are affected globally. The development of new strategies for treatment and/or prevention, and the identification of biomarkers for patient stratification and early detection of disease inception are essential to reducing the impact of lung diseases. The successful translation of research into clinical practice requires a detailed understanding of the underlying biology. In this regard, the advent of next-generation sequencing and mass spectrometry has led to the generation of an unprecedented amount of data spanning multiple layers of biological regulation (genome, epigenome, transcriptome, proteome, metabolome and microbiome). Dealing with this wealth of data requires sophisticated bioinformatics and statistical tools. Here, we review the basic concepts in bioinformatics and genomic data analysis and illustrate the application of these tools to further our understanding of lung diseases. We also highlight the potential for data integration of multi-omic profiles and computational drug repurposing to define disease subphenotypes and match them to targeted therapies, paving the way for personalized medicine.

PMID: 30218470 [PubMed - as supplied by publisher]

Ex vivo drug sensitivity testing as a means for drug repurposing in esophageal adenocarcinoma.

PLoS One. 2018;13(9):e0203173

Authors: Lohse I, Al-Ali H, Volmar CH, D Alvarez Trotta A, Brothers SP, Capobianco AJ, Wahlestedt C

Abstract
BACKGROUND: Esophageal cancer remains one of the hardest cancers to treat with rising incidence rates, low overall survival and high levels of treatment resistance. The lack of clinically available biomarkers hinder diagnosis and treatment stratification. While large scale sequencing approaches have uncovered a number of molecular makers, little has translated in the routine treatment of esophageal cancer patients.
MATERIAL AND METHODS: We evaluate the treatment response towards a panel of 215 FDA-approved and 163 epigenetic compounds of 4 established and 2 patient-derived esophageal cancer cell lines. Cell viability was evaluated after 72h of treatment using cell titer glow. The drug sensitivity testing results for gemcitabine and cisplatin were validated using clonogenic assays.
RESULTS: The tested cell lines display different drug sensitivity profiles, although we found compounds that display efficacy in all of the tested established or patient-derived cell lines. Clonogenic assays confirmed the validity of the drug sensitivity testing results. Using the epigenetic library, we observed high sensitivity towards a number of epigenetic modifiers.
DISCUSSION: Ex vivo drug sensitivity testing may present a viable option for the treatment stratification of esophageal cancer patients and holds the potential to greatly improve patient outcome while reducing treatment toxicity.

PMID: 30212533 [PubMed - in process]

The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase.

Tuberculosis (Edinb). 2018 Sep;112:98-109

Authors: Mori G, Orena BS, Franch C, Mitchenall LA, Godbole AA, Rodrigues L, Aguilar-Pérez C, Zemanová J, Huszár S, Forbak M, Lane TR, Sabbah M, Deboosere N, Frita R, Vandeputte A, Hoffmann E, Russo R, Connell N, Veilleux C, Jha RK, Kumar P, Freundlich JS, Brodin P, Aínsa JA, Nagaraja V, Maxwell A, Mikušová K, Pasca MR, Ekins S

Abstract
The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of 14C-uracil and 14C-leucine similar to the effect of rifampicin, a known inhibitor of M. tuberculosis RNA polymerase. Surprisingly, the co-administration of pyronaridine (2.5 μg/ml) and rifampicin resulted in in vitro synergy with an MIC 0.0019-0.0009 μg/mL. This was mirrored in a THP-1 macrophage infection model, with a 16-fold MIC reduction for rifampicin when the two compounds were co-administered versus rifampicin alone. Docking pyronaridine in M. tuberculosis RNA polymerase suggested the potential for it to bind outside of the RNA polymerase rifampicin binding pocket. Pyronaridine was also found to have activity against a M. tuberculosis clinical isolate resistant to rifampicin, and when combined with rifampicin (10% MIC) was able to inhibit M. tuberculosis RNA polymerase in vitro. All these findings, and in particular the synergistic behavior with the antitubercular rifampicin, inhibition of RNA polymerase in combination in vitro and its current use as a treatment for malaria, may suggest that pyronaridine could also be used as an adjunct for treatment against M. tuberculosis infection. Future studies will test potential for in vivo synergy, clinical utility and attempt to develop pyronaridine analogs with improved potency against M. tuberculosis RNA polymerase when combined with rifampicin.

PMID: 30205975 [PubMed - in process]

Repositioning of molsidomine for its efficacy in diabetes induced erectile dysfunction in rats: In silico, in vitro and in vivo approach.

Pharmacol Rep. 2018 Apr;70(2):309-315

Authors: Minaz N, Razdan R, Pathak L

Abstract
BACKGROUND: Well known risk factors for diabetic erectile dysfunction include impaired nitric oxide synthesis and endothelial dysfunction. We proposed to evaluate the efficacy of nitric oxide donor, molsidomine in rat model of diabetic erectile dysfunction.
METHODS: Streptozotocin (52mg/kg, ip) induced diabetic male rats were treated with molsidomine (5 and 10mg/kg, po) for 8 weeks. The sexual behaviour of male rat in presence of the female rat in oestrous phase was observed at the end of study. The effect of treatment on serum testosterone level, sperm parameters and penile tissue histopathology was also evaluated. Further anti-inflammatory activity and antioxidant potential of molsidomine was evaluated by in vitro method. In silico docking study was carried out to appreciate binding conformation of the molsidomine to its plausible target, phosphodiesterase enzyme.
RESULTS: Molsidomine significantly and dose dependently increased sexual behaviour, sperm count and serum testosterone level in diabetic rats. Further, the protective effect of molsidomine was also substantiated by pathological changes in the architect of the penile tissue. Molsidomine showed good membrane stability accounting for its significant anti-inflammatory action and also significantly scavenged DPPH radical activity showing its antioxidant action. Molsidomine was found to settle well in the active site of PDE-5 enzyme with less binding affinity than the standard drug sildenafil.
CONCLUSION: The results highlight the rationale behind the repositioning of molsidomine therapy for the management of diabetic erectile dysfunction.

PMID: 29477039 [PubMed - indexed for MEDLINE]

Pharmacologic Treatment of Polycystic Ovary Syndrome: Alternate and Future Paths.

Semin Reprod Med. 2017 07;35(4):326-343

Authors: Duguech LMM, Legro RS

PMID: 29036740 [PubMed - indexed for MEDLINE]

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases.

Proteins. 2018 Sep 08;:

Authors: Krishna Deepak RNV, Abdullah A, Talwar P, Fan H, Ravanan P

Abstract
The regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed five compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that four out of the five drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the four compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs. This article is protected by copyright. All rights reserved.

PMID: 30194780 [PubMed - as supplied by publisher]

Virtual screening and drug repositioning as strategies for the discovery of new antifungal inhibitors of oxidosqualene cyclase.

J Steroid Biochem Mol Biol. 2018 Sep 04;:

Authors: Rabelo VW, de Jesus Viegas D, Tucci EMN, Romeiro NC, Abreu PA

Abstract
Candidiasis is the most common fungal infection in immunocompromised patients, and Candida albicans is the fourth leading agent of nosocomial infections. Mortality from this infection is significant; however, the therapeutic treatment is limited, which demands the search for new drugs and new targets. In this context, oxidosqualene cyclase (OSC) catalyzes the cyclization of the 2,3-oxidosqualene to form lanosterol, an intermediate of ergosterol biosynthesis. Therefore, this enzyme constitutes an attractive therapeutic target. Thus, the aim of this study is to identify potential inhibitors of C. albicans OSC (CaOSC) from a marketed drugs database in order to discover new antifungal agents. The CaOSC 3D model was constructed using the Swiss-Model server and important features for CaOSC inhibition were identified by molecular docking of known inhibitors using Autodock Vina 1.1.2. Subsequently, virtual screening helped to identify calcitriol, the active form of vitamin D, and other four drugs, as potential inhibitors of CaOSC. The selected drugs presented an interesting pattern of interactions with this enzyme, including hydrogen bond with Asp450, a key residue in the active site. Thus, the antifungal activity of calcitriol was evaluated in vitro against Candida spp strains. Calcitriol showed antifungal activity against C. albicans and C. tropicalis, which reinforces the potential of this compound as candidate of CaOSC inhibitor. In short, the present study provides important insights for the development of new oxidosqualene cyclase inhibitors as antifungals.

PMID: 30193921 [PubMed - as supplied by publisher]

Online structure-based screening of purchasable approved drugs and natural compounds: retrospective examples of drug repositioning on cancer targets.

Oncotarget. 2018 Aug 17;9(64):32346-32361

Authors: Lagarde N, Rey J, Gyulkhandanyan A, Tufféry P, Miteva MA, Villoutreix BO

Abstract
Drug discovery is a long and difficult process that benefits from the integration of virtual screening methods in experimental screening campaigns such as to generate testable hypotheses, accelerate and/or reduce the cost of drug development. Current drug attrition rate is still a major issue in all therapeutic areas and especially in the field of cancer. Drug repositioning as well as the screening of natural compounds constitute promising approaches to accelerate and improve the success rate of drug discovery. We developed three compounds libraries of purchasable compounds: Drugs-lib, FOOD-lib and NP-lib that contain approved drugs, food constituents and natural products, respectively, that are optimized for structure-based virtual screening studies. The three compounds libraries are implemented in the MTiOpenScreen web server that allows users to perform structure-based virtual screening computations on their selected protein targets. The server outputs a list of 1,500 molecules with predicted binding scores that can then be processed further by the users and purchased for experimental validation. To illustrate the potential of our service for drug repositioning endeavours, we selected five recently published drugs that have been repositioned in vitro and/or in vivo on cancer targets. For each drug, we used the MTiOpenScreen service to screen the Drugs-lib collection against the corresponding anti-cancer target and we show that our protocol is able to rank these drugs within the top ranked compounds. This web server should assist the discovery of promising molecules that could benefit patients, with faster development times, and reduced costs and risk.

PMID: 30190791 [PubMed]

Prediction of Non-coding RNAs as Drug Targets.

Adv Exp Med Biol. 2018;1094:109-115

Authors: Jiang W, Lv Y, Wang S

Abstract
MiRNA is a class of small non-coding RNA molecule that regulates gene expression at post-transcriptional level. Increasing evidences show aberrant expression of miRNAs in a variety of diseases. Targeting the dysregulated miRNAs with small molecule drugs has become a novel therapeutics for many human diseases, especially cancers. In this chapter, we introduced a series of computational studies for prediction of small molecule and miRNA associations. Based on different hypotheses, such as transcriptional response similarity, functional consistence or network closeness, the small molecule-miRNA networks were constructed and further analyzed. In addition, several resources that collected experimentally validated relationships or computational predicted associations between small molecules and miRNAs were provided. Collectively, these computational frameworks and databases pave a new way for miRNA-targeted therapy and drug repositioning.

PMID: 30191492 [PubMed - in process]

Using predicate and provenance information from a knowledge graph for drug efficacy screening.

J Biomed Semantics. 2018 Sep 06;9(1):23

Authors: Vlietstra WJ, Vos R, Sijbers AM, van Mulligen EM, Kors JA

Abstract
BACKGROUND: Biomedical knowledge graphs have become important tools to computationally analyse the comprehensive body of biomedical knowledge. They represent knowledge as subject-predicate-object triples, in which the predicate indicates the relationship between subject and object. A triple can also contain provenance information, which consists of references to the sources of the triple (e.g. scientific publications or database entries). Knowledge graphs have been used to classify drug-disease pairs for drug efficacy screening, but existing computational methods have often ignored predicate and provenance information. Using this information, we aimed to develop a supervised machine learning classifier and determine the added value of predicate and provenance information for drug efficacy screening. To ensure the biological plausibility of our method we performed our research on the protein level, where drugs are represented by their drug target proteins, and diseases by their disease proteins.
RESULTS: Using random forests with repeated 10-fold cross-validation, our method achieved an area under the ROC curve (AUC) of 78.1% and 74.3% for two reference sets. We benchmarked against a state-of-the-art knowledge-graph technique that does not use predicate and provenance information, obtaining AUCs of 65.6% and 64.6%, respectively. Classifiers that only used predicate information performed superior to classifiers that only used provenance information, but using both performed best.
CONCLUSION: We conclude that both predicate and provenance information provide added value for drug efficacy screening.

PMID: 30189889 [PubMed - in process]

Histone Deacetylase Inhibitors and Diabetic Kidney Disease.

Int J Mol Sci. 2018 Sep 05;19(9):

Authors: Hadden MJ, Advani A

Abstract
Despite recent clinical trial advances and improvements in clinical care, kidney disease due to diabetes remains the most common cause of chronic kidney failure worldwide. In the search for new treatments, recent attentions have turned to drug repurposing opportunities, including study of the histone deacetylase (HDAC) inhibitor class of agents. HDACs are a group of enzymes that remove functional acetyl groups from histone and non-histone proteins and they can affect cellular function through both epigenetic and non-epigenetic means. Over the past decade, several HDAC inhibitors have been adopted into clinical practice, primarily for the treatment of hematological malignancy, whereas other existing therapies (for instance valproate) have been found to have HDAC inhibitory effects. Here we review the current HDAC inhibitors in the clinic and under development; the literature evidence supporting the renoprotective effects of HDAC inhibitors in experimental diabetic kidney disease; and the adverse effect profiles that may prevent existing therapies from entering the clinic for this indication. Whereas recent research efforts have shed light on the fundamental actions of HDACs in the diabetic kidney, whether these efforts will translate into novel therapies for patients will require more specific and better-tolerated therapies.

PMID: 30189630 [PubMed - in process]

Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling.

J Ethnopharmacol. 2018 May 10;217:23-35

Authors: Sinha S, Sharma S, Vora J, Shah H, Srivastava A, Shrivastava N

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer.
AIM OF THE STUDY: We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance.
MATERIALS AND METHODS: Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells.
RESULTS: Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer-related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells.
CONCLUSIONS: Collectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer.

PMID: 29427634 [PubMed - indexed for MEDLINE]

The potential to treat lung cancer via inhalation of repurposed drugs.

Adv Drug Deliv Rev. 2018 Sep 03;:

Authors: Lee WH, Loo CY, Ghadiri M, Leong CR, Young PM, Traini D

Abstract
Lung cancer is a highly invasive and prevalent disease with ineffective first-line treatment and remains the leading cause of cancer death in men and women. Despite the improvements in diagnosis and therapy, the prognosis and outcome of lung cancer patients is still poor. This could be associated with the lack of effective first-line oncology drugs, formation of resistant tumors and non-optimal administration route. Therefore, the repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration could be investigated as an alternative to improve lung cancer therapy. This review describes the rationale and development of repositioning of drugs for lung cancer treatment with emphasis on inhalation. The review includes the current progress of repurposing non-cancer drugs, as well as current chemotherapeutics for lung malignancies via inhalation. Several potential non-cancer drugs such as statins, itraconazole and clarithromycin, that have demonstrated preclinical anti-cancer activity, are also presented. Furthermore, the potential challenges and limitations that might hamper the clinical translation of repurposed oncology drugs are described.

PMID: 30189271 [PubMed - as supplied by publisher]

New drug candidates for depression - a nationwide population-based study.

Acta Psychiatr Scand. 2018 Sep 04;:

Authors: V Kessing L, Rytgaard HC, Gerds TA, Berk M, Ekstrøm CT, Andersen PK

Abstract
OBJECTIVE: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers.
METHODS: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants.
RESULTS: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression.
CONCLUSION: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential.

PMID: 30182363 [PubMed - as supplied by publisher]

High-Throughput Screening of Entamoeba Identifies Compounds Which Target Both Life Cycle Stages and Which Are Effective Against Metronidazole Resistant Parasites.

Front Cell Infect Microbiol. 2018;8:276

Authors: Ehrenkaufer GM, Suresh S, Solow-Cordero D, Singh U

Abstract
Neglected tropical diseases, especially those caused by parasites, are significantly underserved by current drug development efforts, mostly due to the high costs and low economic returns. One method for lowering the costs of drug discovery and development for these diseases is to repurpose drugs developed for other indications. Here, we present the results of a screen of five repurposed drug libraries to identify potential new lead compounds to treat amebiasis, a disease that affects tens of millions of people and causes ~100,000 deaths annually. E. histolytica, the causative agent of amebiasis, has two major life cycle stages, the trophozoite and the cyst. The current primary treatment for amebiasis, nitroimidazole compounds, do not eliminate parasites from the colonic lumen, necessitating a multi-drug treatment regimen. We aimed to address this problem by screening against both life stages, with the aim of identifying a single drug that targets both. We successfully identified eleven compounds with activity against both cysts and trophozoites, as well as multiple compounds that killed trophozoites with improved efficacy over existing drugs. Two lead compounds (anisomycin and prodigiosin) were further characterized for activity against metronidazole (MNZ) resistant parasites and mature cysts. Anisomycin and prodigiosin were both able to kill MNZ resistant parasites while prodigiosin and its analog obatoclax were active against mature cysts. This work confirms the feasibility of identifying drugs that target both Entamoeba trophozoites and cysts, and is an important step toward developing improved treatment regimens for Entamoeba infection.

PMID: 30175074 [PubMed - in process]

Prediction of Novel Drugs and Diseases for Hepatocellular Carcinoma Based on Multi-Source Simulated Annealing Based Random Walk.

J Med Syst. 2018 Sep 01;42(10):188

Authors: Ibrahim SJA, Thangamani M

Abstract
Computational techniques for foreseeing drug-disease associations by means of incorporating gene expression as well as biological network give high intuitions to the composite associations amongst targets, drugs, disease genes in addition to the diseases at a system level. Hepatocellular Carcinoma (HCC) is a malevolent tumor containing a greater rate of sickness as well as mortality. In the present work, an Integrative framework is presented with the aim of resolving this problem, for identifying new Drugs for HCC dependent upon Multi-Source Random Walk (PD-MRW), in which score the complete drugs by means of building the drug-drug similarity network. On the other hand, the collection of clinical phenotypes as well as drug side effects in combination with patient-specific genetic info. As a result, the formation of disease-drug networks that denotes the prescriptions, which are allotted to treat those diseases that are not concentrated by means of PD-MRW model. With the aim of overcoming this issue, this research offers an integrative framework for foreseeing new drugs as well as diseases for HCC dependent upon Multi-Source Simulated Annealing based Random Walk (PDD-MSSARW). Primarily, build a Gene-Gene Weighted Interaction Network (GWIN), dependent upon the gene expression as well as protein interaction network. After that, construct a drug-drug similarity network, dependent upon multi-source random walk in GWIN, disease-drug similarity network with the help of Similarity Weighted Bipartite Graph Network (SWBGN) that is build up in which the nodes are drugs as well as association among one node to another node that explains the disease diagnoses. Lastly, dependent upon the known drugs for HCC, score the entire drugs in the similarity networks. The sturdiness of the likelihoods, their overlap with those stated in Comparative Toxicogenomics Database (CTD) as well as kinds of literature, and their enhanced KEGG pathway illustrate PDD-MSSARW method be capable of efficiently find out novel drug signs.

PMID: 30173379 [PubMed - in process]