A drug repositioning approach reveals Streptococcus mutans is susceptible to a diverse range of established antimicrobials and non-antibiotics.

Antimicrob Agents Chemother. 2017 Oct 23;:

Authors: Saputo S, Faustoferri RC, Quivey RG

Abstract
Streptococcus mutans is the primary causative agent of dental caries and contributes to the multispecies biofilm known as dental plaque. An adenylate kinase-based assay was optimized for S. mutans to detect cell lysis when exposed to the Selleck library of 853 FDA-approved drugs, in, to our knowledge, the first high-throughput drug screen in S. mutans We found 126 drugs with activity against S. mutans planktonic cultures and they were classified into six categories: antibacterials (61), antineoplastics (23), ion channel effectors (9), other antimicrobials (7), antifungals (6), and other (20). These drugs were also tested for activity against S. mutans biofilm cultures, and 24 compounds were found to inhibit biofilm formation, 6 killed pre-existing biofilms, 84 exhibited biofilm inhibition and killing activity, and 12 had no activity against biofilms. The activity of 9 selected compounds that exhibited antimicrobial activity were further characterized for their activity against S. mutans planktonic and biofilm cultures. Together, our results suggest that S. mutans exhibits a susceptibility profile to a diverse array of established and novel antibacterials.

PMID: 29061736 [PubMed - as supplied by publisher]

Drug repurposing: An approach to tackle drug resistance in S. typhimurium.

J Cell Biochem. 2017 Oct 23;:

Authors: Preethi B, Shanthi V, Suthindhiran K, Ramanathan K

Abstract
Drug resistant S. typhimurium pose important public health problem. The development of effective drugs with novel mechanism(s) of action is needed to overcome issues pertaining to drug resistance. Drug repurposing based on computational analyses is considered a viable alternative strategy to circumvent this issue. In this context, 1309 FDA-approved drugs molecules from Mantra 2.0 database were analysed for this study, against S. typhimurium. Sixteen compounds having similar profiles of gene expression as quinolones were identified from the database, Mantra 2.0. Further, the pharmacophore characteristics of each resultant molecule were identified and compared with the features of nalidixic acid, using the PharamGist program. Subsequently, the activities of these compounds against S. typhimurium DNA gyrase were identified, using molecular docking study. Side effects analysis was also performed for the identified compounds. Molecular dynamics simulation was carried out for the compound to validate its binding efficiency. Further, characterization of screened compound revealed IC50 values in micromolar concentration range, of which flufenamic acid showed comparable in vitro activity alongside ciprofloxacin and nalidixic acid. Thus represent interesting starting points for further optimization against S. typhimurium infections. It may be noted that the results we have obtained are the first experimental evidence of flufenamic acid activity against S. typhimurium. This article is protected by copyright. All rights reserved.

PMID: 29058787 [PubMed - as supplied by publisher]

Integrative cancer pharmacogenomics to establish drug mechanism of action: drug repurposing.

Pharmacogenomics. 2017 Oct 23;:

Authors: El-Hachem N, Ba-Alawi W, Smith I, Mer AS, Haibe-Kains B

PMID: 29057710 [PubMed - as supplied by publisher]

Computational drug repositioning for rare diseases in the era of precision medicine.

Drug Discov Today. 2017 Oct 18;:

Authors: Delavan B, Roberts R, Huang R, Bao W, Tong W, Liu Z

Abstract
There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases. First, we summarize the current genome landscape of rare diseases. Second, we propose several promising bioinformatics approaches and pipelines for computational drug repositioning for rare diseases. Finally, we discuss recent regulatory incentives and other enablers in rare disease drug development and outline the remaining challenges.

PMID: 29055182 [PubMed - as supplied by publisher]

Drug-target interaction prediction: A Bayesian ranking approach.

Comput Methods Programs Biomed. 2017 Dec;152:15-21

Authors: Peska L, Buza K, Koller J

Abstract
BACKGROUND AND OBJECTIVE: In silico prediction of drug-target interactions (DTI) could provide valuable information and speed-up the process of drug repositioning - finding novel usage for existing drugs. In our work, we focus on machine learning algorithms supporting drug-centric repositioning approach, which aims to find novel usage for existing or abandoned drugs. We aim at proposing a per-drug ranking-based method, which reflects the needs of drug-centric repositioning research better than conventional drug-target prediction approaches.
METHODS: We propose Bayesian Ranking Prediction of Drug-Target Interactions (BRDTI). The method is based on Bayesian Personalized Ranking matrix factorization (BPR) which has been shown to be an excellent approach for various preference learning tasks, however, it has not been used for DTI prediction previously. In order to successfully deal with DTI challenges, we extended BPR by proposing: (i) the incorporation of target bias, (ii) a technique to handle new drugs and (iii) content alignment to take structural similarities of drugs and targets into account.
RESULTS: Evaluation on five benchmark datasets shows that BRDTI outperforms several state-of-the-art approaches in terms of per-drug nDCG and AUC. BRDTI results w.r.t. nDCG are 0.929, 0.953, 0.948, 0.897 and 0.690 for G-Protein Coupled Receptors (GPCR), Ion Channels (IC), Nuclear Receptors (NR), Enzymes (E) and Kinase (K) datasets respectively. Additionally, BRDTI significantly outperformed other methods (BLM-NII, WNN-GIP, NetLapRLS and CMF) w.r.t. nDCG in 17 out of 20 cases. Furthermore, BRDTI was also shown to be able to predict novel drug-target interactions not contained in the original datasets. The average recall at top-10 predicted targets for each drug was 0.762, 0.560, 1.000 and 0.404 for GPCR, IC, NR, and E datasets respectively.
CONCLUSIONS: Based on the evaluation, we can conclude that BRDTI is an appropriate choice for researchers looking for an in silico DTI prediction technique to be used in drug-centric repositioning scenarios. BRDTI Software and supplementary materials are available online at www.ksi.mff.cuni.cz/∼peska/BRDTI.

PMID: 29054256 [PubMed - in process]

A Systematic Review of Computational Drug Discovery, Development, and Repurposing for Ebola Virus Disease Treatment.

Molecules. 2017 Oct 20;22(10):

Authors: Schuler J, Hudson ML, Schwartz D, Samudrala R

Abstract
Ebola virus disease (EVD) is a deadly global public health threat, with no currently approved treatments. Traditional drug discovery and development is too expensive and inefficient to react quickly to the threat. We review published research studies that utilize computational approaches to find or develop drugs that target the Ebola virus and synthesize its results. A variety of hypothesized and/or novel treatments are reported to have potential anti-Ebola activity. Approaches that utilize multi-targeting/polypharmacology have the most promise in treating EVD.

PMID: 29053626 [PubMed - in process]

A novel chemoradiation targeting stem and nonstem pancreatic cancer cells by repurposing disulfiram.

Cancer Lett. 2017 Nov 28;409:9-19

Authors: Cong J, Wang Y, Zhang X, Zhang N, Liu L, Soukup K, Michelakos T, Hong T, DeLeo A, Cai L, Sabbatino F, Ferrone S, Lee H, Levina V, Fuchs B, Tanabe K, Lillemoe K, Ferrone C, Wang X

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of 8% and is projected to be the second leading cause of cancer death by 2030, underscoring the urgency to develop new strategies to improve current therapeutic modalities for PDAC. Targeting pancreatic cancer stem cells (PCSCs), which are resistant to radiation and chemotherapy, is a promising strategy. A novel approach which can be readily clinically translated is to repurpose disulfiram (DSF), a drug for treating alcoholism, to target PCSCs. Chemoradiation or the combination of chemotherapy agents FOLFIRINOX, currently standard care for PDAC, can increase stemness in some established or primary PDAC cell lines. However, DSF in the presence of exogenously or endogenously supplied copper (Cu), when combined with chemotherapy or chemoradiation, targets both PCSCs and nonstem PDAC cells. Previously, we demonstrated that DSF/Cu effectively targets breast cancer stem cells in the context of fractionated radiation (FIR) by inhibiting the NF-κB-stemness gene pathway. Therefore, the hypothesis that PCSCs can be effectively targeted by incorporating DSF/Cu into the standard chemoradiation regimen consisting of 5-FU and FIR was investigated and found to be effective in vitro in targeting PCSCs, identified as either ALDH(bright) or CD24+/CD44+/ESA+ or sphere-forming cells, as well as nonstem PDAC cells. In vivo, the combination of IR+5-FU+DSF/Cu was more effective (72.46%) than either IR+5-FU (30.32%) or IR+FOLFIRINOX therapy (43.04%) in inhibiting growth of the mouse Panc02 tumor. These encouraging results provide a solid foundation for clinical trials to improve the outcomes of the current standard chemoradiation therapy regimen for PDAC.

PMID: 28864067 [PubMed - indexed for MEDLINE]

Transcriptomic-Guided Drug Repositioning Supported by a New Bioinformatics Search Tool: geneXpharma.

OMICS. 2017 Oct;21(10):584-591

Authors: Turanli B, Gulfidan G, Arga KY

Abstract
Drug repositioning is an innovative approach to identify new therapeutic indications for existing drugs. Drug repositioning offers the promise of reducing drug development timeframes and costs, and because it involves drugs that are already in the clinic, it might remedy some of the drug safety challenges traditionally associated with drug candidates that are not yet available in the clinic. The gene-by-drug interactions are an important dimension of optimal drug repositioning and development strategies. While gene-by-drug interactions have been curated and presented in various databases, novel bioinformatics tools and approaches are timely, and required with a specific focus to support drug positioning. We report, in this study, the design of a public web-accessible transcriptomic-/gene expression-guided pharmaceuticals search tool, geneXpharma ( www.genexpharma.org ). GeneXpharma is a public platform with user-centric interface that provides statistically evaluated gene expressions and their drug interactions for 48 diseases under seven different disease categories. GeneXpharma is designed and organized to generate hypotheses on druggable genome within the disease-gene-drug triad and thus, help repositioning of drugs against diseases. The search system accommodates various entry points using drugs, genes, or diseases, which then enable researchers to extract drug repurposing candidates and readily export for further evaluation. Future developments aim to improve the geneXpharma algorithm, enrich its content, and enhance the website interface through addition of network visualizations and graphical display items. Bioinformatics search tools can help enable the convergence of drug repositioning and gene-by-drug interactions so as to further optimize drug development efforts in the future.

PMID: 29049014 [PubMed - in process]

A profound computational study to prioritize the disease-causing mutations in PRPS1 gene.

Metab Brain Dis. 2017 Oct 18;:

Authors: Agrahari AK, Sneha P, George Priya Doss C, Siva R, Zayed H

Abstract
Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited congenital neurological disorders, affecting approximately 1 in 2500 in the US. About 80 genes were found to be in association with CMT. The phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is an essential enzyme in the primary stage of de novo and salvage nucleotide synthesis. The mutations in the PRPS1 gene leads to X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), PRS super activity, Arts syndrome, X-linked deafness-1, breast cancer, and colorectal cancer. In the present study, we obtained 20 missense mutations from UniProt and dbSNP databases and applied series of comprehensive in silico prediction methods to assess the degree of pathogenicity and stability. In silico tools predicted four missense mutations (D52H, M115 T, L152P, and D203H) to be potential disease causing mutations. We further subjected the four mutations along with native protein to 50 ns molecular dynamics simulation (MDS) using Gromacs package. The resulting trajectory files were analyzed to understand the stability differences caused by the mutations. We used the Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), solvent accessibility surface area (SASA), Covariance matrix, Principal Component Analysis (PCA), Free Energy Landscape (FEL), and secondary structure analysis to assess the structural changes in the protein upon mutation. Our study suggests that the four mutations might affect the PRPS1 protein function and stability of the structure. The proposed study may serve as a platform for drug repositioning and personalized medicine for diseases that are caused by the PRPS1 deficiency.

PMID: 29047041 [PubMed - as supplied by publisher]

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing.

Cancer Metastasis Rev. 2017 Oct 18;:

Authors: Soave CL, Guerin T, Liu J, Dou QP

Abstract
In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

PMID: 29047025 [PubMed - as supplied by publisher]

Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade.

Front Pharmacol. 2017;8:710

Authors: Torrisi SA, Salomone S, Geraci F, Caraci F, Bucolo C, Drago F, Leggio GM

Abstract
Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R) and D4 receptor (D4R) antagonist activity. Multiple lines of evidence point to D3R as a valid therapeutic target for the treatment of several neuropsychiatric disorders including schizophrenia. In the present study, we tested the hypothesis that buspirone, behaving as dopamine D3R antagonist, may have antipsychotic-like activity. Materials and Methods: Effects of acute administration of buspirone was assessed on a wide-range of schizophrenia-relevant abnormalities induced by a single administration of the non-competitive NMDAR antagonist MK-801, in both wild-type mice (WT) and D3R-null mutant mice (D3R(-/-)). Results: Buspirone (3 mg⋅kg(-1), i.p.) was devoid of cataleptogenic activity in itself, but resulted effective in counteracting disruption of prepulse inhibition (PPI), hyperlocomotion and deficit of temporal order recognition memory (TOR) induced by MK-801 (0.1 mg⋅kg(-1), i.p.) in WT mice. Conversely, in D3R(-/-) mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion. Conclusion: Taken together, these results indicate, for the first time, that buspirone, might be a potential therapeutic medication for the treatment of schizophrenia. In particular, buspirone, through its D3R antagonist activity, may be a useful tool for improving the treatment of cognitive deficits in schizophrenia that still represents an unmet need of this disease.

PMID: 29046641 [PubMed]

Antiseptic effects of dabrafenib on TGFBIp-induced septic responses.

Chem Biol Interact. 2017 Oct 14;:

Authors: Lee IC, Bae JS

Abstract
Transforming growth factor-β-induced protein (TGFBIp), an extracellular protein, is expressed on several cell types in response to TGF-β stimulation. Human umbilical vein endothelial cell (HUVEC)-derived TGFBIp functions as a mediator of sepsis. Screening of bioactive compound libraries is an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases (drug repositioning). Dabrafenib (DAB), a B-Raf inhibitor, was initially used for treating metastatic melanoma. The present study determined whether DAB modulated TGFBIp-mediated septic responses in HUVECs and in mice. Antiseptic functions of DAB were examined by measuring permeability, leukocyte adhesion and migration, and proinflammatory protein activation in TGFBIp-stimulated HUVECs and mice. In addition, beneficial effects of DAB on survival rate were examined using a mouse model of sepsis. We found that DAB inhibited TGFBIp-induced vascular barrier disruption, cell adhesion molecule (CAM) expression, and neutrophil adhesion/transendothelial migration toward human endothelial cells. DAB also suppressed TGFBIp-induced hyperpermeability and leukocyte migration in vivo. These results suggest that DAB exerts anti-inflammatory effects by inhibiting hyperpermeability, CAM expression, and leukocyte adhesion and migration, indicating its utility for treating vascular inflammatory diseases.

PMID: 29042256 [PubMed - as supplied by publisher]

Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities.

Int J Epidemiol. 2017 Oct 11;:

Authors: Walker VM, Davey Smith G, Davies NM, Martin RM

Abstract
Identification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current observational research methods are subject to several biases. These include confounding by indication, reverse causality and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evidence from this method and other approaches, in the spirit of triangulation, to improve causal inferences concerning drug effects. MR addresses some of the limitations associated with the existing methods in this field. Furthermore, it can be applied either before or after approval of the drug, and could therefore prevent the potentially harmful exposure of patients in clinical trials and beyond. The potential of MR as a pharmacovigilance and drug repurposing tool is yet to be realized, and could both help prevent adverse drug events and identify novel indications for existing drugs in the future.

PMID: 29040597 [PubMed - as supplied by publisher]

Insights from pharmacological similarity of epigenetic targets in epipolypharmacology.

Drug Discov Today. 2017 Oct 13;:

Authors: Naveja JJ, Medina-Franco JL

Abstract
As the number of compounds tested against epigenetic targets grows, exploration of the possible associations in chemical space among these targets could lead to the identification of new drugs or new designs of epipolypharmacological molecules. Thus, here we review the compound-epitarget associations of the numerous public databases available. Specifically, we explore the structure-multitarget activity relationships and diversity of over 7000 compounds tested against 52 epigenetic-related targets. We found that, whereas inhibitors of histone deacetylases and other epigenetic targets clustered in the chemical space, the chemical space of inhibitors of different DNA methyltransferases (DNMTs) did not overlap, indicating DNMT selectivity. These and other compound-epitarget relationships discussed here could be useful for both drug repurposing and the rational design of epipolypharmacological compounds.

PMID: 29038074 [PubMed - as supplied by publisher]

Repurposing FDA-approved drugs for anti-aging therapies.

Biogerontology. 2016 Nov;17(5-6):907-920

Authors: Snell TW, Johnston RK, Srinivasan B, Zhou H, Gao M, Skolnick J

Abstract
There is great interest in drugs that are capable of modulating multiple aging pathways, thereby delaying the onset and progression of aging. Effective strategies for drug development include the repurposing of existing drugs already approved by the FDA for human therapy. FDA approved drugs have known mechanisms of action and have been thoroughly screened for safety. Although there has been extensive scientific activity in repurposing drugs for disease therapy, there has been little testing of these drugs for their effects on aging. The pool of FDA approved drugs therefore represents a large reservoir of drug candidates with substantial potential for anti-aging therapy. In this paper we employ FINDSITE(comb), a powerful ligand homology modeling program, to identify binding partners for proteins produced by temperature sensing genes that have been implicated in aging. This list of drugs with potential to modulate aging rates was then tested experimentally for lifespan and healthspan extension using a small invertebrate model. Three protein targets of the rotifer Brachionus manjavacas corresponding to products of the transient receptor potential gene 7, ribosomal protein S6 polypeptide 2 gene, or forkhead box C gene, were screened against a compound library consisting of DrugBank drugs including 1347 FDA approved, non-nutraceutical molecules. Twenty nine drugs ranked in the top 1 % for binding to each target were subsequently included in our experimental analysis. Continuous exposure of rotifers to 1 µM naproxen significantly extended rotifer mean lifespan by 14 %. We used three endpoints to estimate rotifer health: swimming speed (mobility proxy), reproduction (overall vitality), and mitochondria activity (cellular senescence proxy). The natural decline in swimming speed with aging was more gradual when rotifers were exposed to three drugs, so that on day 6, mean swimming speed of females was 1.19 mm/s for naproxen (P = 0.038), 1.20 for fludarabine (P = 0.040), 1.35 for hydralazine (P = 0.038), as compared to 0.88 mm/s in the control. The average reproduction of control females in the second half of their reproductive lifespan was 1.08 per day. In contrast, females treated with 1 µM naproxen produced 1.4 offspring per day (P = 0.027) and females treated with 10 µM fludarabine or 1 µM hydralazine produced 1.72 (P = <0.001) and 1.66 (P = 0.001) offspring per day, respectively. Mitochondrial activity naturally declines with rotifer aging, but B. manjavacas treated with 1 µM hydralazine or 10 µM fludarabine retained 49 % (P = 0.038) and 89 % (P = 0.002) greater mitochondria activity, respectively, than untreated controls. Our results demonstrate that coupling computation to experimentation can quickly identify new drug candidates with anti-aging potential. Screening drugs for anti-aging effects using a rotifer bioassay is a powerful first step in identifying compounds worthy of follow-up in vertebrate models. Even if lifespan extension is not observed, certain drugs could improve healthspan, slowing age-dependent losses in mobility and vitality.

PMID: 27484416 [PubMed - indexed for MEDLINE]

PEGylated chitosan nanoparticles potentiate repurposing of ormeloxifene in breast cancer therapy.

Nanomedicine (Lond). 2016 Aug;11(16):2147-69

Authors: Agrawal S, Ahmad H, Dwivedi M, Shukla M, Arya A, Sharma K, Lal J, Dwivedi AK

Abstract
AIM: Development and optimization of ormeloxifene-loaded PEGylated chitosan nanoparticles (CNPs) for enhancing its literature profound therapeutic activity against breast cancer.
METHODS: CNPs were prepared by ionotropic gelation method and characterized.
RESULTS: Optimized formulation (CNPs10) had average 304 nm particle size with 0.247 polydispersity index and spherical shape with +31 mV surface charge. CNPs10 had 88.37% entrapment efficiency and 20.93% loading efficiency. CNPs10 demonstrated dose-dependent enhancement in cytotoxicity, cellular uptake, apoptosis, disruption of mitochondrial membrane potential and activation of caspase-3 in breast cancer MDA-MB-231 and MCF-7 cells over free ormeloxifene. In vivo studies divulged improved pharmacokinetic parameters, reduced toxicity, suppressed tumor burden and increased survival in CNPs10-treated female Sprague-Dawley rats.
CONCLUSION: PEGylated CNPs enhanced anticancer activity of ormeloxifene.

PMID: 27463533 [PubMed - indexed for MEDLINE]

Designing Dietary Recommendations Using System Level Interactomics Analysis and Network-Based Inference.

Front Physiol. 2017;8:753

Authors: Zheng T, Ni Y, Li J, Chow BKC, Panagiotou G

Abstract
Background: A range of computational methods that rely on the analysis of genome-wide expression datasets have been developed and successfully used for drug repositioning. The success of these methods is based on the hypothesis that introducing a factor (in this case, a drug molecule) that could reverse the disease gene expression signature will lead to a therapeutic effect. However, it has also been shown that globally reversing the disease expression signature is not a prerequisite for drug activity. On the other hand, the basic idea of significant anti-correlation in expression profiles could have great value for establishing diet-disease associations and could provide new insights into the role of dietary interventions in disease. Methods: We performed an integrated analysis of publicly available gene expression profiles for foods, diseases and drugs, by calculating pairwise similarity scores for diet and disease gene expression signatures and characterizing their topological features in protein-protein interaction networks. Results: We identified 485 diet-disease pairs where diet could positively influence disease development and 472 pairs where specific diets should be avoided in a disease state. Multiple evidence suggests that orange, whey and coconut fat could be beneficial for psoriasis, lung adenocarcinoma and macular degeneration, respectively. On the other hand, fructose-rich diet should be restricted in patients with chronic intermittent hypoxia and ovarian cancer. Since humans normally do not consume foods in isolation, we also applied different algorithms to predict synergism; as a result, 58 food pairs were predicted. Interestingly, the diets identified as anti-correlated with diseases showed a topological proximity to the disease proteins similar to that of the corresponding drugs. Conclusions: In conclusion, we provide a computational framework for establishing diet-disease associations and additional information on the role of diet in disease development. Due to the complexity of analyzing the food composition and eating patterns of individuals our in silico analysis, using large-scale gene expression datasets and network-based topological features, may serve as a proof-of-concept in nutritional systems biology for identifying diet-disease relationships and subsequently designing dietary recommendations.

PMID: 29033850 [PubMed]

HMG-CoA reductase inhibition delays DNA repair and promotes senescence after tumor irradiation.

Mol Cancer Ther. 2017 Oct 13;:

Authors: Efimova EV, Ricco N, Labay E, Mauceri HJ, Flor AC, Ramamurthy A, Sutton HG, Weichselbaum RR, Kron SJ

Abstract
Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSBs) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs and success rates of drug development. In a prior screen where we tracked resolution of ionizing radiation-induced foci (IRIF) as a proxy for DSB repair, we had identified pitavastatin (Livalo), an HMG-CoA reductase inhibitor commonly used for lipid lowering, as a candidate radiosensitizer. Here we report that pitavastatin and other lipophilic statins are potent inhibitors of DSB repair in breast and melanoma models both in vitro and in vivo. When combined with ionizing radiation, pitavastatin increased persistent DSBs, induced senescence and enhanced acute effects of radiation on radioresistant melanoma tumors. shRNA knockdown implicated HMG-CoA reductase, farnesyl diphosphate synthase, and protein farnesyl transferase in IRIF resolution, DSB repair and senescence. These data confirm on-target activity of statins, though via inhibition of protein prenylation rather than cholesterol biosynthesis. In light of prior studies demonstrating enhanced efficacy of radiotherapy in patients taking statins, this work argues for clinical evaluation of lipophilic statins as non-toxic radiosensitizers to enhance the benefits of image-guided radiotherapy.

PMID: 29030460 [PubMed - as supplied by publisher]

Eco-pharma of approved drug focused on mitochondria fission.

Nihon Yakurigaku Zasshi. 2017;149(6):269-273

Authors: Shimauchi T, Nishimura A, Ishikawa T, Nishida M

PMID: 28626119 [PubMed - indexed for MEDLINE]

Web-based drug repurposing tools: a survey.

Brief Bioinform. 2017 Oct 06;:

Authors: Sam E, Athri P

Abstract
Drug repurposing (a.k.a. drug repositioning) is the search for new indications or molecular targets distinct from a drug's putative activity, pharmacological effect or binding specificities. With the ever-increasing rates of termination of drugs in clinical trials, drug repositioning has risen as one of the effective solutions against the risk of drug failures. Repositioning finds a way to reverse the grim but real trend that Eroom's law portends for the pharmaceutical and biotech industry, and drug discovery in general. Further, the advent of high-throughput technologies to explore biological systems has enabled the generation of zeta bytes of data and a massive collection of databases that store them. Computational analytics and mining are frequently used as effective tools to explore this byzantine series of biological and biomedical data. However, advanced computational tools are often difficult to understand or use, thereby limiting their accessibility to scientists without a strong computational background. Hence it is of great importance to build user-friendly interfaces to extend the user-base beyond computational scientists, to include life scientists who may have deeper chemical and biological insights. This survey is focused on systematically presenting the available Web-based tools that aid in repositioning drugs.

PMID: 29028878 [PubMed - as supplied by publisher]