A novel anti-cancer role of β-apopicropodophyllin against non-small cell lung cancer cells.

Toxicol Appl Pharmacol. 2018 Aug 28;:

Authors: Kim JY, Cho JH, Choi JR, Shin HJ, Song JY, Hwang SG, Um HD, Do Yoo Y, Kim J, Park JK

Abstract
We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of β-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC50 values of 16.9, 13.1 and 17.1 nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2α, CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.

PMID: 30170025 [PubMed - as supplied by publisher]

Binding site matching in rational drug design: algorithms and applications.

Brief Bioinform. 2018 Aug 31;:

Authors: Naderi M, Lemoine JM, Govindaraj RG, Kana OZ, Feinstein WP, Brylinski M

Abstract
Interactions between proteins and small molecules are critical for biological functions. These interactions often occur in small cavities within protein structures, known as ligand-binding pockets. Understanding the physicochemical qualities of binding pockets is essential to improve not only our basic knowledge of biological systems, but also drug development procedures. In order to quantify similarities among pockets in terms of their geometries and chemical properties, either bound ligands can be compared to one another or binding sites can be matched directly. Both perspectives routinely take advantage of computational methods including various techniques to represent and compare small molecules as well as local protein structures. In this review, we survey 12 tools widely used to match pockets. These methods are divided into five categories based on the algorithm implemented to construct binding-site alignments. In addition to the comprehensive analysis of their algorithms, test sets and the performance of each method are described. We also discuss general pharmacological applications of computational pocket matching in drug repurposing, polypharmacology and side effects. Reflecting on the importance of these techniques in drug discovery, in the end, we elaborate on the development of more accurate meta-predictors, the incorporation of protein flexibility and the integration of powerful artificial intelligence technologies such as deep learning.

PMID: 30169563 [PubMed - as supplied by publisher]

Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis.

BMJ Open. 2018 Aug 30;8(8):e021944

Authors: Connick P, De Angelis F, Parker RA, Plantone D, Doshi A, John N, Stutters J, MacManus D, Prados Carrasco F, Barkhof F, Ourselin S, Braisher M, Ross M, Cranswick G, Pavitt SH, Giovannoni G, Gandini Wheeler-Kingshott CA, Hawkins C, Sharrack B, Bastow R, Weir CJ, Stallard N, Chandran S, Chataway J, UK Multiple Sclerosis Society Clinical Trials Network

Abstract
INTRODUCTION: The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).
METHODS AND ANALYSIS: Patients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.
ETHICS AND DISSEMINATION: MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.
TRIAL REGISTRATION NUMBERS: NCT01910259; 2012-005394-31; ISRCTN28440672.

PMID: 30166303 [PubMed - in process]

Niclosamide Induces Epiboly Delay During Early Zebrafish Embryogenesis.

Toxicol Sci. 2018 Aug 27;:

Authors: Vliet SM, Dasgupta S, Volz DC

Abstract
Niclosamide is an antihelminthic drug used worldwide for the treatment of tapeworm infections. Recent drug repurposing screens have revealed that niclosamide exhibits diverse mechanisms of action and, as a result, demonstrates promise for a number of applications, including the treatment of cancer, bacterial infections, and Zika virus. As new applications of niclosamide will require non-oral delivery routes that may lead to exposure in utero, the objective of this study was to investigate the mechanism of niclosamide toxicity during early stages of embryonic development. Using zebrafish as a model, we found that niclosamide induced a concentration-dependent delay in epiboly progression during late-blastula and early-gastrula, an effect that was dependent on exposure during the maternal-to-zygotic transition - a period characterized by degradation of maternally-derived transcripts, zygotic genome activation, and initiation of cell motility. Moreover, we found that niclosamide did not affect embryonic oxygen consumption, suggesting that oxidative phosphorylation - a well-established target for niclosamide within intestinal parasites - may not play a role in niclosamide-induced epiboly delay. However, mRNA-sequencing revealed that niclosamide exposure during blastula and early-gastrula significantly impacted the timing of zygotic genome activation as well as the abundance of cytoskeleton- and cell cycle regulation-specific transcripts. In addition, we found that niclosamide inhibited tubulin polymerization in vitro, suggesting that niclosamide-induced delays in epiboly progression may, in part, be driven by disruption of microtubule formation and cell motility within the developing embryo.

PMID: 30165700 [PubMed - as supplied by publisher]

CNS repurposing - Potential new uses for old drugs: Examples of screens for Alzheimer's disease, Parkinson's disease and spasticity.

Neuropharmacology. 2018 Aug 27;:

Authors: Parsons CG

Abstract
Drug repurposing is recently gaining increasing attention, not just from pharmaceutical companies but also from government agencies in an attempt to generate new medications to address increasing unmet medical needs in a cost effective and expedite manner. There are several approaches to identify novel indications for known drugs. Many are based on rational selection e.g. the known or a new mechanism of action of a drug. This review will focus rather on phenotypic or high content screening of compounds in models that are believed to be predictive of effectiveness of compounds irrespective of their mechanism of action. Three short cases studies of screens for Alzheimer's disease, Parkinson's disease and spasticity will be given as examples.

PMID: 30165077 [PubMed - as supplied by publisher]

Pathway-Based Drug Repositioning for Breast Cancer Molecular Subtypes.

Front Pharmacol. 2018;9:905

Authors: Mejía-Pedroza RA, Espinal-Enríquez J, Hernández-Lemus E

Abstract
Breast cancer is a major public health problem which treatment needs new pharmacological options. In the last decades, during the postgenomic era new theoretical and technological tools that give us novel and promising ways to address these problems have emerged. In this work, we integrate several tools that exploit disease-specific experimental transcriptomic results in addition to information from biological and pharmacological data bases obtaining a contextual prioritization of pathways and drugs in breast cancer subtypes. The usefulness of these results should be evaluated in terms of drug repurposing in each breast cancer molecular subtype therapy. In favor of breast cancer patients, this methodology could be further developed to provide personalized treatment schemes. The latter are particularly needed in those breast cancer subtypes with limited therapeutic options or those who have developed resistance to the current pharmacological schemes.

PMID: 30158869 [PubMed]

Interactions of Selective Serotonin Reuptake Inhibitors (SSRIs) with β-Amyloid.

ACS Chem Neurosci. 2018 Aug 30;:

Authors: Tin G, Mohamed T, Shakeri A, Pham AT, Rao PPN

Abstract
Treating Alzheimer's disease (AD) is a major challenge at the moment with no new drugs available to cure this devastating neurodegenerative disorder. In this regard, "drug repurposing" which aims to determine novel therapeutic usage for drugs already approved by the regulatory agencies is a pragmatic approach to discover novel treatment strategies. Selective serotonin reuptake inhibitors (SSRIs) are a known class of US FDA approved drugs used in the treatment of depression. We investigated the ability of SSRIs fluvoxamine, fluoxetine, paroxetine, sertraline and escitalopram on Aβ42 aggregation and fibrillogenesis. Remarkably, the aggregation kinetic experiments carried out demonstrate the anti-Aβ42 aggregation activity of SSRIs fluoxetine, paroxetine and sertraline at all the tested concentrations (1, 10, 50 and 100 µM). Both fluoxetine and paroxetine were identified as the most promising SSRIs showing 74.8% and 76% inhibition of Aβ42 aggregation at 100 µM. The transmission electron microscopy (TEM) experiments and dot-blot study also demonstrates the ability of fluoxetine and paroxetine to prevent Aβ42 aggregation and fibrillogenesis providing further evidence. Investigating the binding interactions of fluoxetine and paroxetine in the Aβ42 oligomer and fibril models derived from the solid-state NMR structure suggests that these SSRIs interact at a region close to the N-terminal (Lys16-Glu22) in the S-shaped cross-β-strand assembly and reduce Aβ42 fibrillogenesis. Based on this study, a pharmacophore model is proposed which shows that the minimum structural requirements to design novel Aβ42 aggregation inhibitors include the presence of one ionizable group, one hydrophobic group, two aromatic rings and two hydrogen bond donor groups. These studies demonstrate that SSRIs have the potential to prevent Aβ42 aggregation by direct binding and could be beneficial to AD patients on SSRIs.

PMID: 30157623 [PubMed - as supplied by publisher]

L-Lysine-α-Oxidase: Acidovorax citrulli Bacterium Inhibitor.

Bull Exp Biol Med. 2018 Mar;164(4):459-461

Authors: Smirnova IP, Karimova EV, Shneider YA, Volina EG

Abstract
Studies of the effects of Trichoderma harzianum Rifai F-180 culture fluid concentrate containing L-lysine-α-oxidase antitumor enzyme produced by the fungus and the homogenous enzyme, on ultrahazardous bacterium Acidovorax citrulli demonstrated the antibacterial activity of the concentrate. Trichoderma harzianum Rifai F-180 producing L-lysine-α-oxidase was cultured in a technological device at G. K. Skryabin Institute of Biochemistry and. Physiology of Microorganisms, Russian Academy of Sciences. Activity of L-lysine-α-oxidase in the resulted culture fluid concentrate was 0.54 U/ml, activity of the homogenous enzyme was 50 U/mg.

PMID: 29504100 [PubMed - indexed for MEDLINE]

Harnessing the biological complexity of Big Data from LINCS gene expression signatures.

PLoS One. 2018;13(8):e0201937

Authors: Musa A, Tripathi S, Kandhavelu M, Dehmer M, Emmert-Streib F

Abstract
Gene expression profiling using transcriptional drug perturbations are useful for many biomedical discovery studies including drug repurposing and elucidation of drug mechanisms (MoA) and many other pharmacogenomic applications. However, limited data availability across cell types has severely hindered our capacity to progress in these areas. To fill this gap, recently, the LINCS program generated almost 1.3 million profiles for over 40,000 drug and genetic perturbations for over 70 different human cell types, including meta information about the experimental conditions and cell lines. Unfortunately, Big Data like the ones generated from the ongoing LINCS program do not enable easy insights from the data but possess considerable challenges toward their analysis. In this paper, we address some of these challenges. Specifically, first, we study the gene expression signature profiles from all cell lines and their perturbagents in order to obtain insights in the distributional characteristics of available conditions. Second, we investigate the differential expression of genes for all cell lines obtaining an understanding of condition dependent differential expression manifesting the biological complexity of perturbagents. As a result, our analysis helps the experimental design of follow-up studies, e.g., by selecting appropriate cell lines.

PMID: 30157183 [PubMed - in process]

Drug Repurposing for Duchenne Muscular Dystrophy: The Monoamine Oxidase B Inhibitor Safinamide Ameliorates the Pathological Phenotype in mdx Mice and in Myogenic Cultures From DMD Patients.

Front Physiol. 2018;9:1087

Authors: Vitiello L, Marabita M, Sorato E, Nogara L, Forestan G, Mouly V, Salviati L, Acosta M, Blaauw B, Canton M

Abstract
Oxidative stress and mitochondrial dysfunction play a crucial role in the pathophysiology of muscular dystrophies. We previously reported that the mitochondrial enzyme monoamine oxidase (MAO) is a relevant source of reactive oxygen species (ROS) not only in murine models of muscular dystrophy, in which it directly contributes to contractile impairment, but also in muscle cells from collagen VI-deficient patients. Here, we now assessed the efficacy of a novel MAO-B inhibitor, safinamide, using in vivo and in vitro models of Duchenne muscular dystrophy (DMD). Specifically, we found that administration of safinamide in 3-month-old mdx mice reduced myofiber damage and oxidative stress and improved muscle functionality. In vitro studies with myogenic cultures from mdx mice and DMD patients showed that even cultured dystrophic myoblasts were more susceptible to oxidative stress than matching cells from healthy donors. Indeed, upon exposure to the MAO substrate tyramine or to hydrogen peroxide, DMD muscle cells displayed a rise in ROS levels and a consequent mitochondrial depolarization. Remarkably, both phenotypes normalized when cultures were treated with safinamide. Given that safinamide is already in clinical use for neurological disorders, our findings could pave the way toward a promising translation into clinical trials for DMD patients as a classic case of drug repurposing.

PMID: 30154729 [PubMed]

Oral Paracetamol for Patent Ductus Arteriosus Rescue Closure.

Pediatr Cardiol. 2018 Jan;39(1):183-190

Authors: Pharande P, Watson H, Tan K, Sehgal A

Abstract
The objective of this study was to ascertain the efficacy of oral paracetamol in closing a symptomatic patent ductus arteriosus (PDA) when used as 'rescue' option. After obtaining ethics approval, a retrospective appraisal of the data from April 2014 to July 2015 was performed. Infants who were administered oral paracetamol either after unsuccessful therapy with ibuprofen or where it was considered contraindicated were included. A previously published echocardiographic scoring schema to stratify for ductal disease severity was used. Using univariate analysis, characteristics of infants with successful closure were compared with partial (a priori reduction in composite score by ≥ 50% of pretreatment) or no closure. Twenty infants with gestation age and birthweight of 25.7 ± 1.5 weeks and 724.1 ± 143 g, respectively, were studied. Complete closure was noted in 10 (50%) infants with additional four infants showing a significant reduction in haemodynamic shunting. Gestational age at birth and at therapy, chronological age at therapy, birthweight and total fluid intake were comparable between the two groups. The pre-therapy composite score had a significant association with successful closure (the higher the echocardiographic score, the lesser the closure). Concomitant furosemide therapy and late-onset sepsis had a high likelihood ratio of unsuccessful closure (11.01 [2-tailed, p = 0.005] and 5.3 [2-tailed, p = 0.07]), respectively. Oral paracetamol may be a possible therapeutic option in premature infants where therapy with first-line agents is unsuccessful or contraindicated. Concomitant sepsis and furosemide administration may affect successful therapy.

PMID: 29043398 [PubMed - indexed for MEDLINE]

Turning omics data into therapeutic insights.

Curr Opin Pharmacol. 2018 Aug 24;42:95-101

Authors: Kedaigle A, Fraenkel E

Abstract
Omics technologies have made it easier and cheaper to evaluate thousands of biological molecules at once. These advances have led to novel therapies approved for use in the clinic, elucidated the mechanisms behind disease-associated mutations, led to increased accuracy in disease subtyping and personalized medicine, and revealed novel uses and treatment regimes for existing drugs through drug repurposing and pharmacology studies. In this review, we summarize some of these milestones and discuss the potential of integrative analyses that combine multiple data types for further advances.

PMID: 30149217 [PubMed - as supplied by publisher]

In Silico-Based Repositioning of Phosphinothricin as a Novel Technetium-99m Imaging Probe with Potential Anti-Cancer Activity.

Molecules. 2018 Feb 23;23(2):

Authors: Sakr TM, Khedr MA, Rashed HM, Mohamed ME

Abstract
l-Phosphinothricin (glufosinate or 2-amino-4-((hydroxy(methyl) phosphinyl) butyric acid ammonium salt (AHPB)), which is a structural analog of glutamate, is a recognized herbicide that acts on weeds through inhibition of glutamine synthetase. Due to the structural similarity between phosphinothricin and some bisphosphonates (BPs), this study focuses on investigating the possibility of repurposing phosphinothricin as a bisphosphonate analogue, particularly in two medicine-related activities: image probing and as an anti-cancer drug. As BP is a competitive inhibitor of human farnesyl pyrophosphate synthase (HFPPS), in silico molecular docking and dynamic simulations studies were established to evaluate the binding and stability of phosphinothricin with HFPPS, while the results showed good binding and stability in the active site of the enzyme in relation to alendronate. For the purpose of inspecting bone-tissue accumulation of phosphinothricin, a technetium (99mTc)-phosphinothricin complex was developed and its stability and tissue distribution were scrutinized. The radioactive complex showed rapid, high and sustained uptake into bone tissues. Finally, the cytotoxic activity of phosphinothricin was tested against breast and lung cancer cells, with the results indicating cytotoxic activity in relation to alendronate. All the above results provide support for the use of phosphinothricin as a potential anti-cancer drug and of its technetium complex as an imaging probe.

PMID: 29473879 [PubMed - indexed for MEDLINE]

Convergent downstream candidate mechanisms of independent intergenic polymorphisms between co-classified diseases implicate epistasis among noncoding elements.

Pac Symp Biocomput. 2018;23:524-535

Authors: Han J, Li J, Achour I, Pesce L, Foster I, Li H, Lussier YA

Abstract
Eighty percent of DNA outside protein coding regions was shown biochemically functional by the ENCODE project, enabling studies of their interactions. Studies have since explored how convergent downstream mechanisms arise from independent genetic risks of one complex disease. However, the cross-talk and epistasis between intergenic risks associated with distinct complex diseases have not been comprehensively characterized. Our recent integrative genomic analysis unveiled downstream biological effectors of disease-specific polymorphisms buried in intergenic regions, and we then validated their genetic synergy and antagonism in distinct GWAS. We extend this approach to characterize convergent downstream candidate mechanisms of distinct intergenic SNPs across distinct diseases within the same clinical classification. We construct a multipartite network consisting of 467 diseases organized in 15 classes, 2,358 disease-associated SNPs, 6,301 SNPassociated mRNAs by eQTL, and mRNA annotations to 4,538 Gene Ontology mechanisms. Functional similarity between two SNPs (similar SNP pairs) is imputed using a nested information theoretic distance model for which p-values are assigned by conservative scale-free permutation of network edges without replacement (node degrees constant). At FDR≤5%, we prioritized 3,870 intergenic SNP pairs associated, among which 755 are associated with distinct diseases sharing the same disease class, implicating 167 intergenic SNPs, 14 classes, 230 mRNAs, and 134 GO terms. Co-classified SNP pairs were more likely to be prioritized as compared to those of distinct classes confirming a noncoding genetic underpinning to clinical classification (odds ratio ∼3.8; p≤10-25). The prioritized pairs were also enriched in regions bound to the same/interacting transcription factors and/or interacting in long-range chromatin interactions suggestive of epistasis (odds ratio ∼ 2,500; p≤10-25). This prioritized network implicates complex epistasis between intergenic polymorphisms of co-classified diseases and offers a roadmap for a novel therapeutic paradigm: repositioning medications that target proteins within downstream mechanisms of intergenic disease-associated SNPs. Supplementary information and software: http://lussiergroup.org/publications/disease_class.

PMID: 29218911 [PubMed - indexed for MEDLINE]

Bioinformatic and biological avenues for understanding alcohol use disorder.

Alcohol. 2018 Aug 22;:

Authors: Grantham EK, Farris SP

Abstract
Alcohol Use Disorder (AUD) is a multifarious psychiatric condition resulting from complex relationships between genetics, gene expression, neuroadaptations, and environmental influences. Understanding these complex relationships is essential to uncovering the mechanisms involved in the development and progression of AUD, with the ultimate goal of devising effective behavioral and therapeutic interventions. Technical advances in the fields of omics-based research and bioinformatics have yielded insights into gene interactions, biological networks, and cellular responses across humans and animal models. This review highlights several of the newly developed sequencing methodologies and resultant discoveries in neuroscience, as well as the importance of a multi-faceted and integrative approach for determining causal factors in AUD.

PMID: 30144960 [PubMed - as supplied by publisher]

DPP-4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high-glucose conditions, potentially through the SIRT1/HIF-1/VEGF pathway.

CNS Neurosci Ther. 2018 Aug 23;:

Authors: Mi DH, Fang HJ, Zheng GH, Liang XH, Ding YR, Liu X, Liu LP

Abstract
BACKGROUND: Vascular disease in diabetes, for example, stroke, presents a significant public health burden. Recently, the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin has been found to counteract stroke among diabetic patients, showing great promise in drug repurposing and indication expansion. However, the molecular basis of this protection mechanism remains unknown.
METHODS: The expression and localization of DPP-4 in rat brain microvascular endothelial cells (rBMVECs) were assessed with immunofluorescent staining and Western blotting. The effects of DPP-4 inhibitors on cell proliferation and migration of rBMVECs were determined using MTT and transwell assays, separately. The influence of DPP-4 inhibition on the expression of molecular markers (eg, VEGF, eNOS, HIF-1α. SIRT1) was examined at both mRNA and protein levels with qRT-PCR and Western blotting, individually.
RESULTS: DPP-4 inhibitors (40 nmol/L linagliptin, 30 μmol/L berberine) offer protection from hypoxia/high glucose induced impairments in the proliferation and migration of rBMVECs. Treatment with DPP-4 inhibitors counteracted the attenuating effects of hypoxic/high-glucose conditions on the expression of VEGF, eNOS, HIF-1α, and SIRT1, which can be completely eliminated by the inhibition of SIRT1 with 1 mmol/L nicotinamide.
CONCLUSIONS: The protection of rBMVECs from hypoxia/high-glucose induced impairment by DPP-4 inhibitors may be mediated by the SIRT1/HIF-1α/VEGF pathway.

PMID: 30136405 [PubMed - as supplied by publisher]

Computational drug repurposing to predict approved and novel drug-disease associations.

J Mol Graph Model. 2018 Aug 14;85:91-96

Authors: Khalid Z, Sezerman OU

Abstract
The Drug often binds to more than one targets defined as polypharmacology, one application of which is drug repurposing also referred as drug repositioning or therapeutic switching. The traditional drug discovery and development is a high-priced and tedious process, thus making drug repurposing a popular alternate strategy. We proposed an integrative method based on similarity scheme that predicts approved and novel Drug targets with new disease associations. We combined PPI, biological pathways, binding site structural similarities and disease-disease similarity measures. The results showed 94% Accuracy with 0.93 Recall and 0.94 Precision measure in predicting the approved and novel targets surpassing the existing methods. All these parameters help in elucidating the unknown associations between drug and diseases for finding the new uses for old drugs.

PMID: 30130693 [PubMed - as supplied by publisher]

Recent advances in the machine learning-based drug-target interaction prediction.

Curr Drug Metab. 2018 Aug 20;:

Authors: Zhang W, Lin W, Zhang D, Wang S, Shi J, Niu Y

Abstract
The identification of drug-target interactions is a crucial issue in drug discovery. In recent years, researchers have made great efforts on the drug-target interaction predictions, and developed databases, software and computational methods. In the paper, we review the recent advances of machine learning-based drug-target interaction prediction. First, we briefly introduce the datasets and data, and summarize features for drugs and targets which can be extracted from different data. Since drug-drug similarity and target-target similarity are important for many machine learning prediction models, we introduce how to calculate similarities based on data or features. Different machine learning-based drug-target interaction prediction methods can be proposed by using different features or information. Thus, we summarize, analyze and compare different machine learning-based prediction methods. This study provides the guide to the development of computational methods for the drug-target interaction prediction.

PMID: 30129407 [PubMed - as supplied by publisher]

Review of Drug Repositioning Approaches and Resources.

Int J Biol Sci. 2018;14(10):1232-1244

Authors: Xue H, Li J, Xie H, Wang Y

Abstract
Drug discovery is a time-consuming, high-investment, and high-risk process in traditional drug development. Drug repositioning has become a popular strategy in recent years. Different from traditional drug development strategies, the strategy is efficient, economical and riskless. There are usually three kinds of approaches: computational approaches, biological experimental approaches, and mixed approaches, all of which are widely used in drug repositioning. In this paper, we reviewed computational approaches and highlighted their characteristics to provide references for researchers to develop more powerful approaches. At the same time, the important findings obtained using these approaches are listed. Furthermore, we summarized 76 important resources about drug repositioning. Finally, challenges and opportunities in drug repositioning are discussed from multiple perspectives, including technology, commercial models, patents and investment.

PMID: 30123072 [PubMed - in process]

Drug repurposing: Ibrutinib exhibits immunosuppressive potential in organ transplantation.

Int J Med Sci. 2018;15(11):1118-1128

Authors: Zhang Q, Chen J, Gao H, Zhang S, Zhao C, Zhou C, Wang C, Li Y, Cai Z, Mou L

Abstract
Long-term administration of classic immunosuppressants can induce severe adverse effects. The development of novel immunosuppressants confronts great challenges and opportunities. Ibrutinib, an approved drug for B-cell lineages and chronic graft versus host disease (cGVHD), exhibits immunosuppressive efficacy in autoimmune diseases. Ibrutinib's potential as an immunosuppressant in organ transplantation has not been investigated to date. In a xeno-artery patch model ex vivo, ibrutinib inhibited the proliferation of PBMCs (POD 14-42), mainly CD3+CD4+ and CD3+CD8+ T cells ex vivo. The secretion of cytokines (IL-6, IL-2 and IFN-γ) was suppressed in response to ibrutinib. In allo-skin transplantation models, ibrutinib delayed the rejection of grafted skins. Ibrutinib decreased the amount of T/B cells and lymphocyte infiltration. Altogether, ibrutinib exhibited immunosuppressive potential through cytokine regulation and T cell inhibition ex vivo and in vitro. Repositioning of ibrutinib as an immunosuppressant will greatly facilitate novel immunosuppressant development.

PMID: 30123049 [PubMed - in process]