Filling the gap in CNS drug development: evaluation of the role of drug repurposing.

J Mark Access Health Policy. 2017;5(1):1299833

Authors: Caban A, Pisarczyk K, Kopacz K, Kapuśniak A, Toumi M, Rémuzat C, Kornfeld A

Abstract
Background and objective: Background and objective: Drug repurposing has been considered a cost-effective and reduced-risk strategy for developing new drugs. Little is known and documented regarding the efficiency of repurposing strategies in drug development. The objective of this article is to assess the extent and meaning of this process in the CNS area. Methods: In order to identify repurposed drugs that target the CNS, an extensive search was performed. For each identified case, its initial and target indication, development status and the type of repurposing strategy (repositioning, reformulation or both) was recorded. Results: One hundred and eighteen source products were identified. They were repurposed (mainly repositioned) 203 times with 81 products repurposed once and 38 products repurposed twice or more. The highest number of source drugs originated from the CNS area. Alzheimer's disease was targeted most often. Half of the new indications were approved. Regarding repurposing within the CNS area, epilepsy, schizophrenia and depression were the richest sources of repurposed drugs. Conclusions: Repurposing drugs into CNS is an efficient and very active drug development method, exemplified by the considerable number of new indications that have been found via this strategy, with approximately half of the target indications currently under development.

PMID: 28473889 [PubMed - in process]

Cancer stem cell (CSC) inhibitors: a review of recent patents (2012-2015).

Expert Opin Ther Pat. 2017 May 02;:

Authors: Kharkar PS

Abstract
INTRODUCTION: Cancer stem cells (CSCs) mediate tumor initiation and maintenance. These cells are chemoresistant and possess characteristics such as self-renewal, pluripotency, plasticity and differentiation. They have aberrant or altered signaling pathways depending on tumor microenvironment, tumor type, etc. CSCs are responsible for highly aggressive and invasive form of the disease following chemo- and/or radiotherapy. Eliminating CSCs is likely to improve the survival rate in patients. Several anti-CSC strategies and associated targets have been proposed and validated till date. Areas covered: The main emphasis is on the patent applications/patents filed/granted in the last few years (2012-2015). The anti-CSC agents are discussed under two broad headings - small- and macromolecules. Different subclasses are further elaborated, e.g., kinase inhibitors, polypeptides, etc. Expert opinion: Clinical development of small- and macromolecular anti-CSC therapeutics is underway. Few of these agents act on validated targets such as kinases. Potential problems with these agents can be envisaged based on our understanding of target biology. Other issues governing the choice of small- versus macromolecules include druggability of the target, ease its modulation and the presence of compensatory mechanisms. Drug repurposing can be attempted to discover newer anti-CSC drugs quickly.

PMID: 28460551 [PubMed - as supplied by publisher]

Genomes, structural biology and drug discovery: combating the impacts of mutations in genetic disease and antibiotic resistance.

Biochem Soc Trans. 2017 Apr 15;45(2):303-311

Authors: Pandurangan AP, Ascher DB, Thomas SE, Blundell TL

Abstract
For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future.

PMID: 28408471 [PubMed - indexed for MEDLINE]

In silico drug repurposing of FDA-approved drugs to predict new inhibitors for drug resistant T315I mutant and wild-type BCR-ABL1: A virtual screening and molecular dynamics study.

J Mol Graph Model. 2017 Apr 13;74:234-240

Authors: Sohraby F, Bagheri M, Aliyar M, Aryapour H

Abstract
The BCR-ABL fusion gene is one of the major causes of 95% of Chronic Myeloid Leukemia (CML). While, BCR-ABL protein is currently being used as a major target to treat CML. Although, current FDA-approved drugs such as; Imatinib and Nilotinib have stupendously improved the patients 5-year's survival rates, the drug resistance has dramatically reduced their effects. So, more accurate and effective alternative treatments are crucially needed. To address this issue, we screened the FDA-approved drugs by virtual screening and binding free energy calculations to identify new inhibitors for the wild-type and T315I gatekeeper mutant ABL1. It was invigorating to identify that chlorohexidine, paromomycin and deferoxamine could inhibit the wild-type ABL1, while chlorohexidine and ritonavir could inhibit the T315I mutant ABL1. The applications of these newly identified drugs are not just an effortless hypothesis in drug discovery. These drugs can be evaluated in phase 2 clinical trials after a simple kinase selectivity assay.

PMID: 28458002 [PubMed - as supplied by publisher]

Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation.

Mol Pharmacol. 2016 Jun;89(6):630-44

Authors: Kazemi Z, Bergmayr C, Prchal-Murphy M, Javaheri T, Themanns M, Pham HT, Strohmaier W, Sexl V, Freissmuth M, Zebedin-Brandl E

Abstract
Activation of Gs-coupled receptors enhances engraftment of hematopoietic stem and progenitor cells (HSPCs). We tested the hypothesis that treprostinil, a prostacyclin analog approved for the treatment of pulmonary hypertension, can be repurposed to improve hematopoietic stem cell transplantation. Murine and human HSPCs were isolated from bone marrow and umbilical cord blood, respectively. Prostanoid receptor agonists and the combination thereof with forskolin were tested for their capacity to stimulate [(3)H]cAMP accumulation in HSPCs. Three independent approaches were employed to verify the ability of agonist-activated HSPCs to reconstitute the bone marrow in lethally irradiated recipient mice. The underlying mechanism was explored in cellular migration assays and by blocking C-X-C motif chemokine receptor 4 (CXCR4). Among several prostanoid agonists tested in combination with forskolin, treprostinil was most efficacious in raising intracellular cAMP levels in murine and human HPSCs. Injection of murine and human HSPCs, which had been pretreated with treprostinil and forskolin, enhanced survival of lethally irradiated recipient mice. Survival was further improved if recipient mice were subcutaneously administered treprostinil (0.15 mg kg(-1) 8 h(-1)) for 10 days. This regimen also reduced the number of HSPCs required to rescue lethally irradiated mice. Enhanced survival of recipient mice was causally related to treprostinil-enhanced CXCR4-dependent migration of HSPCs. Treprostinil stimulates the engraftment of human and murine hematopoietic stem cells without impairing their capacity for self-renewal. The investigated dose range corresponds to the dose approved for human use. Hence, these findings may be readily translated into a clinical application.

PMID: 26989084 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2017/04/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Repurposing of Anticancer Drugs for the Treatment of Bacterial Infections.

Curr Top Med Chem. 2017;17(10):1157-1176

Authors: Soo VW, Kwan BW, Quezada H, Castillo-Juárez I, Pérez-Eretza B, García-Contreras SJ, Martínez-Vázquez M, Wood TK, García-Contreras R

Abstract
Despite the fact that bacterial infections are one of the leading causes of death worldwide and that mortality rates are increasing at alarming rates, no new antibiotics have been produced by the pharmaceutical industry in more than a decade. The situation is so dire that the World Health Organization warned that we may enter a "post-antibiotic era" within this century; accordingly, bacteria resistant against all known antibiotics are becoming common and already producing untreatable infections. Although several novel approaches to combat bacterial infections have been proposed, they have yet to be implemented in clinical practice. Hence, we propose that a more plausible and faster approach is the utilization of drugs originally developed for other purposes besides antimicrobial activity. Among these are some anticancer molecules proven effective in vitro for eliminating recalcitrant, multidrug tolerant bacteria; some of which also protect animals from infections and recently are undergoing clinical trials. In this review, we highlight the similarities between cancer cells/tumors and bacterial infections, and present evidence that supports the utilization of some anticancer drugs, including 5-fluorouracil (5-FU), gallium (Ga) compounds, and mitomycin C, as antibacterials. Each of these drugs has some promising properties such as broad activity (all three compounds), dual antibiotic and antivirulence properties (5-FU), efficacy against multidrug resistant strains (Ga), and the ability to kill metabolically dormant persister cells which cause chronic infections (mitomycin C).

PMID: 27697046 [PubMed - indexed for MEDLINE]

Translational science approach for assessment of cardiovascular effects and proarrhythmogenic potential of the beta-3 adrenergic agonist mirabegron.

J Pharmacol Toxicol Methods. 2017 Apr 20;:

Authors: Korstanje C, Suzuki M, Yuno K, Sato S, Ukai M, Schneidkraut MJ, Yan GX

Abstract
INTRODUCTION: Translational assessment of cardiac safety parameters is a challenge in clinical development of beta-3 adrenoceptor agonists. The preclinical tools are presented that were used for assessing human safety for mirabegron.
METHODS: Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (IKr, IKs, Ito, INa, and ICa,L), on QT-interval, subendocardial APD90, Tpeak-end interval, and arrhythmia's in ventricular dog wedge tissue in vitro and on cardiovascular function (BP, HR, and QTc) in conscious dogs.
RESULTS: In conscious dogs, mirabegron (0.01-10mg/kg, p.o.) dose-dependently increased HR, reduced SBP but DBP was unchanged. Propranolol blocked the decrease in SBP and attenuated HR increase at 100mg/kg mirabegron. Mirabegron, at 30, 60, or 100mg/kg, p.o., had no significant effect on the QTc interval. In paced dog ventricular wedge, neither mirabegron nor metabolites M5, M11, M12, M14, and M16 prolonged QT, altered transmural dispersion of repolarization, induced premature ventricular contractions, or induced ventricular tachycardia. Mirabegron nor its metabolites inhibited IKr, IKs, Ito INa, or ICa,L at clinically relevant concentrations.
DISCUSSION: Up to exposure levels well exceeding human clinical exposure no discernible effects on ion channel conductance or on arrhythmogenic parameters in ventricular wedge resulted for mirabegron, or its main metabolites, confirming human cardiac safety findings. In vivo, dose-related increases in HR with effects markedly higher than seen clinically, was mediated in part by cross-activation of beta-1 adrenoceptors. This non-clinical cardiac safety test program therefore proved predictive for human cardiac safety for mirabegron.

PMID: 28434969 [PubMed - as supplied by publisher]

The Molecular Revolution in Cutaneous Biology: Emerging Landscape in Genomic Dermatology: New Mechanistic Ideas, Gene Editing, and Therapeutic Breakthroughs.

J Invest Dermatol. 2017 May;137(5):e123-e129

Authors: Titeux M, Izmiryan A, Hovnanian A

Abstract
Stunning technological advances in genomics have led to spectacular breakthroughs in the understanding of the underlying defects, biological pathways and therapeutic targets of skin diseases leading to new therapeutic interventions. Next-generation sequencing has revolutionized the identification of disease-causing genes and has a profound impact in deciphering gene and protein signatures in rare and frequent skin diseases. Gene addition strategies have shown efficacy in junctional EB and in recessive dystrophic EB (RDEB). TALENs and Cripsr/Cas9 have emerged as highly efficient new tools to edit genomic sequences to creat new models and to correct or disrupt mutated genes to treat human diseases. Therapeutic approaches have not been limited to DNA modification and strategies at the mRNA, protein and cellular levels have also emerged, some of which have already proven clinical efficacy in RDEB. Improved understanding of the pathogenesis of skin disorders has led to the development of specific drugs or repurposing of existing medicines as in basal cell nevus syndrome, alopecia areata, melanoma and EB simplex. These discoveries pave the way for improved targeted personalized medicine for rare and frequent diseases. It is likely that a growing number of orphan skin diseases will benefit from combinatory new therapies in a near future.

PMID: 28411843 [PubMed - indexed for MEDLINE]

Mechanistic insights into epigenetic modulation of ethanol consumption.

Alcohol. 2017 Mar 12;:

Authors: Ponomarev I, Stelly CE, Morikawa H, Blednov YA, Mayfield RD, Harris RA

Abstract
There is growing evidence that small-molecule inhibitors of epigenetic modulators, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), can reduce voluntary ethanol consumption in animal models, but molecular and cellular processes underlying this behavioral effect are poorly understood. We used C57BL/6J male mice to investigate the effects of two FDA-approved drugs, decitabine (a DNMT inhibitor) and SAHA (an HDAC inhibitor), on ethanol consumption using two tests: binge-like drinking in the dark (DID) and chronic intermittent every other day (EOD) drinking. Decitabine but not SAHA reduced ethanol consumption in both tests. We further investigated decitabine's effects on the brain's reward pathway by gene expression profiling in the ventral tegmental area (VTA), using RNA sequencing and electrophysiological recordings from VTA dopaminergic neurons. Decitabine-induced decreases in EOD drinking were associated with global changes in gene expression, implicating regulation of cerebral blood flow, extracellular matrix organization, and neuroimmune functions in decitabine actions. In addition, an in vivo administration of decitabine shortened ethanol-induced excitation of VTA dopaminergic neurons in vitro, suggesting that decitabine reduces ethanol drinking via changes in the reward pathway. Taken together, our data suggest a contribution of both neuronal and non-neuronal mechanisms in the VTA in the regulation of ethanol consumption. Decitabine and other epigenetic compounds have been approved for cancer treatment, and understanding their mechanisms of actions in the brain may assist in repurposing these drugs and developing novel therapies for central disorders, including drug addiction.

PMID: 28433417 [PubMed - as supplied by publisher]

Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice.

Brain. 2017 Apr 19;:

Authors: Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M, Mallucci GR

Abstract
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.

PMID: 28430857 [PubMed - as supplied by publisher]

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling.

Oncotarget. 2017 Apr 06;:

Authors: Wang Y, Ma H, Zhao C, Liu T, Yan D, Jou D, Li H, Zhang C, Lü J, Li C, Lin J, Li S, Lin L

Abstract
BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine, which is involved in the regulation of differentiation and growth of certain types of tumor cells. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) induced by IL-6 is frequently detected in liver cancer and has emerged as a viable molecular target for liver cancer treatment. However, few inhibitors targeting up-streams of STAT3 are available for the therapy of liver cancer. We reported the discovery of EVISTA (Raloxifene HCl) as novel inhibitor of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Raloxifene in STAT3 signaling or liver cancer cells is still unclear.
RESULTS: Raloxifene inhibited the P-STAT3 stimulated by IL-6, but not the induction of STAT1 and STAT6 phosphorylation by IFN-γ, IFN-α, and IL-4. Raloxifene inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell-lines. Raloxifene inhibited the targets of STAT3, such as Bcl-2, Bcl-xl and survivin and cell viability, cell migration, and colony formation in liver cancer cells. Further, daily administration of Raloxifene suppressed the Hep-G2 tumor growth in mice in vivo.
MATERIALS AND METHODS: The inhibitory effect on STAT3 phosphorylation and activity as well as cell viability, migration, and colony forming ability by Raloxifene was examined in human liver cancer cells. Tumor growth was detected via mouse xenograft tumor mode.
CONCLUSIONS: Our results suggest that Raloxifene is a potent IL-6/GP130 inhibitor and may be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.

PMID: 28430601 [PubMed - as supplied by publisher]

Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2.

J Exp Clin Cancer Res. 2017 Apr 20;36(1):58

Authors: Li W, Zheng M, Wu S, Gao S, Yang M, Li Z, Min Q, Sun W, Chen L, Xiang G, Li H

Abstract
BACKGROUND: Hexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK2 plays a pivotal role in tumor initiation and maintenance, which provides a new target for cancer therapy.
METHODS: Structure-based virtual ligand screening was used in hit identification from ZINC Drug Database. Microscale thermophoresis assay was performed to evaluate the binding affinity. Enzyme inhibition, cytotoxicity, apoptosis, intracellular ATP level, mitochondrial membrane potential (MMP), glucose uptake and lactate production experiments were undertaken in SW480 cells to identify Benz as a HK2 inhibitor. Western blot was used to test protein expression. SW480 cells xenograft mouse models were used for in vivo study. Nano-particles of Benz were prepared to improve the antitumor efficacy and tumor targeting of Benz. HPLC was used to measure the concentration of free Benz in tumor tissues.
RESULTS: Benserazide (Benz), was identified as a selective HK2 inhibitor, could specifically bind to HK2 and significantly inhibit HK2 enzymatic activity in vitro. In addition, Benz reduced glucose uptake, lactate production and intracellular ATP level, and could cause cell apoptosis and an increased loss of MMP as well. In vivo study indicated that intraperitoneal (ip) injection of Benz at 300 and 600 mg/Kg suppressed cancer growth in tumor-bearing mice and no toxicity shown. To further improve the antitumor efficacy and tumor targeting of Benz, nano-particles of Benz was prepared. Liposomal Benz at 100 and 200 mg/Kg performed potent inhibitory effects on tumor-bearing mice, showing reduced dose and better efficacy.
CONCLUSIONS: Our study provides a new direction for the development of Benz and its analogues as novel antitumor agents for cancer therapy.

PMID: 28427443 [PubMed - in process]

Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma.

Oncotarget. 2017 Apr 04;8(14):22811-22824

Authors: Furuta T, Sabit H, Dong Y, Miyashita K, Kinoshita M, Uchiyama N, Hayashi Y, Hayashi Y, Minamoto T, Nakada M

Abstract
BACKGROUND: Glycogen synthase kinase (GSK)-3β has emerged as an appealing therapeutic target for glioblastoma (GBM). Here, we investigated the therapeutic effect of the current approved drugs against GBM via inhibition of GSK3β activity both, in experimental setting and in a clinical study for recurrent GBM patients by repositioning existent drugs in combination with temozolomide (TMZ).
MATERIALS AND METHODS: Progression-free and overall survival rates were compared between patients with low or high expression of active GSK3β in the primary tumor. GBM cells and a mouse model were examined for the effects of GSK3β-inhibitory drugs, cimetidine, lithium, olanzapine, and valproate. The safety and efficacy of the cocktail of these drugs (CLOVA cocktail) in combination with TMZ were tested in the mouse model and in a clinical study for recurrent GBM patients.
RESULTS: Activation of GSK3β in the tumor inversely correlated with patient survival as an independent prognostic factor. CLOVA cocktail significantly inhibited cell invasion and proliferation. The patients treated with CLOVA cocktail in combination with TMZ showed increased survival compared to the control group treated with TMZ alone.
CONCLUSIONS: Repositioning of the GSK3β-inhibitory drugs improved the prognosis of refractory GBM patients with active GSK3β in tumors. Combination of CLOVA cocktail and TMZ is a promising approach for recurrent GBM.

PMID: 28423558 [PubMed - in process]

Drug Repurposing Patent Applications October-December 2016.

Assay Drug Dev Technol. 2017 Apr;15(3):120-126

Authors: Mucke HAM

PMID: 28418694 [PubMed - in process]

Validating the Predicted Effect of Astemizole and Ketoconazole Using a Drosophila Model of Parkinson's Disease.

Assay Drug Dev Technol. 2017 Apr;15(3):106-112

Authors: Styczyńska-Soczka K, Zechini L, Zografos L

Abstract
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically. In this work, we utilize a transgenic Drosophila model of Parkinson's disease, made by expressing human alpha-synuclein in the Drosophila brain, to validate two repurposed compounds: astemizole and ketoconazole. Both have been computationally predicted to have an ameliorative effect on Parkinson's disease, but neither had been tested using an in vivo model of the disease. After treating the flies in parallel, results showed that both drugs rescue the motor phenotype that is developed by the Drosophila model with age, but only ketoconazole treatment reversed the increased dopaminergic neuron death also observed in these models, which is a hallmark of Parkinson's disease. In addition to validating the predicted improvement in Parkinson's disease symptoms for both drugs and revealing the potential neuroprotective activity of ketoconazole, these results highlight the value of Drosophila models of Parkinson's disease as key tools in the context of in vivo drug discovery, drug repurposing, and prioritization of hits, especially when coupled with computational predictions.

PMID: 28418693 [PubMed - in process]

Drug Repurposing Patent Applications January-March 2017.

Assay Drug Dev Technol. 2017 Apr;15(3):127-132

Authors: Mucke HAM

PMID: 28418692 [PubMed - in process]

Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses.

Molecules. 2016 Jun 28;21(7):

Authors: Fattori V, Hohmann MS, Rossaneis AC, Pinho-Ribeiro FA, Verri WA

Abstract
In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders.

PMID: 27367653 [PubMed - indexed for MEDLINE]

Some Remarks on Prediction of Drug-Target Interaction with Network Models.

Curr Top Med Chem. 2017 Apr 14;:

Authors: Zhang SW, Yan XY

Abstract
System-level understanding of the relationships between drugs and targets is very important for enhancing drug research, especially for drug function repositioning. The experimental methods used to determine drug-target interactions are usually time-consuming, tedious and expensive, and sometimes lack reproducibility. Thus, it is highly desired to develop computational methods for efficiently and effectively analyzing and detecting new drug-target interaction pairs. With the explosive growth of different types of omics data, such as genome, pharmacology, phenotypic, and other kinds of molecular networks, numerous computational approaches have been developed to predict drug-target interactions (DTI). In this review, we make a survey on the recent advances in predicting drug-target interaction with network-based models from the following aspects: i) Available public data sources and benchmark datasets, ii) Drug/target similarity metrics, iii) Network construction, iv) Common network algorithms, v) Performance comparison of existing network-based DTI predictors.

PMID: 28413948 [PubMed - as supplied by publisher]

Molecular therapies for inherited epidermolysis bullosa.

G Ital Dermatol Venereol. 2016 Aug;151(4):397-402

Authors: Has C

Abstract
Inherited epidermolysis bullosa (EB) comprises rare genetic disorders characterized by formation of blisters and erosions of skin and mucous membranes after minor mechanical trauma. The molecular basis and the pathomechanisms of the main EB types have been largely deciphered in the past decades. The burden of the disease is high and quality of life strongly affected. The treatment is still symptomatic aiming to support wound healing and resolve complications. Numerous experimental therapeutic approaches for EB have been explored in the last years, most of them dedicated to dystrophic EB. Although gene and cell therapies have been already applied in patients, molecular therapies including gene editing and repurposing of small molecules are currently very attractive. Recent data on the effect of small molecules, like aminoglycosides and angiotensin receptor blockers in preclinical models for dystrophic EB are encouraging. The efficacy in patients remains to be proven in clinical trials. Therapeutic efficacy, as well as unexpected outcomes must be carefully monitored.

PMID: 27149615 [PubMed - indexed for MEDLINE]