Molecular Topology and other Promiscuity Determinants as Predictors of Therapeutic Class- A Theoretical Framework to guide Drug Repositioning?

Curr Top Med Chem. 2018 Jul 31;:

Authors: Morales JF, Alberca LN, Chuguransky S, Di Ianni ME, Talevi A, Ruiz ME

Abstract
Much interest has been paid in the last decade on molecular predictors of promiscuity, including molecular weight, log P, molecular complexity, acidity constant and molecular topology, with correlations between promiscuity and those descriptors seemingly being context-dependent. It has been observed that certain therapeutic categories (e.g. mood disorders therapies) display a tendency to include multi-target agents (i.e. selective non-selectivity). Numerous QSAR models based on topological descriptors suggest that the topology of a given drug could be used to infer its therapeutic applications. Here, we have used descriptive statistics to explore the distribution of molecular topology descriptors and other promiscuity predictors across different therapeutic categories. Working with the publicly available ChEMBL database and 14 molecular descriptors, both hierarchical and non-hierchical clustering methods were applied to the mean values of the therapeutic categories after the refinement of the database (770 drugs grouped into 34 therapeutic categories). On the other hand, another publicly available database (repoDB) was used to retrieve cases of clinically-approved drug repositionings that could be classified into the therapeutic categories considered by the aforementioned clusters (111 cases), and the correspondence between the two analyzes was evaluated. Interestingly, a 3-cluster hierarchical clustering scheme based on only 14 molecular descriptors linked to promiscuity seem to explain up to 82.9% of approved cases of drug repurposing retrieved of repoDB. Therapeutic categories seem to display distinctive molecular patterns, which could be used as a basis for drug screening and drug design campaigns, and to unveil drug repurposing opportunities between particular therapeutic categories.

PMID: 30068278 [PubMed - as supplied by publisher]

Chemical-induced disease extraction via recurrent piecewise convolutional neural networks.

BMC Med Inform Decis Mak. 2018 Jul 23;18(Suppl 2):60

Authors: Li H, Yang M, Chen Q, Tang B, Wang X, Yan J

Abstract
BACKGROUND: Extracting relationships between chemicals and diseases from unstructured literature have attracted plenty of attention since the relationships are very useful for a large number of biomedical applications such as drug repositioning and pharmacovigilance. A number of machine learning methods have been proposed for chemical-induced disease (CID) extraction due to some publicly available annotated corpora. Most of them suffer from time-consuming feature engineering except deep learning methods. In this paper, we propose a novel document-level deep learning method, called recurrent piecewise convolutional neural networks (RPCNN), for CID extraction.
RESULTS: Experimental results on a benchmark dataset, the CDR (Chemical-induced Disease Relation) dataset of the BioCreative V challenge for CID extraction show that the highest precision, recall and F-score of our RPCNN-based CID extraction system are 65.24, 77.21 and 70.77%, which is competitive with other state-of-the-art systems.
CONCLUSIONS: A novel deep learning method is proposed for document-level CID extraction, where domain knowledge, piecewise strategy, attention mechanism, and multi-instance learning are combined together. The effectiveness of the method is proved by experiments conducted on a benchmark dataset.

PMID: 30066652 [PubMed - in process]

Drug Repurposing in Parkinson's Disease.

CNS Drugs. 2018 Jul 31;:

Authors: Athauda D, Foltynie T

Abstract
The development of an intervention to slow or halt disease progression remains the greatest unmet therapeutic need in Parkinson's disease. Given the number of failures of various novel interventions in disease-modifying clinical trials in combination with the ever-increasing costs and lengthy processes for drug development, attention is being turned to utilizing existing compounds approved for other indications as novel treatments in Parkinson's disease. Advances in rational and systemic drug repurposing have identified a number of drugs with potential benefits for Parkinson's disease pathology and offer a potentially quicker route to drug discovery. Here, we review the safety and potential efficacy of the most promising candidates repurposed as potential disease-modifying treatments for Parkinson's disease in the advanced stages of clinical testing.

PMID: 30066310 [PubMed - as supplied by publisher]

Deciphering cellular biological processes to clinical application: a new perspective for Tα1 treatment targeting multiple diseases.

Expert Opin Biol Ther. 2018 Jul;18(sup1):23-31

Authors: Matteucci C, Argaw-Denboba A, Balestrieri E, Giovinazzo A, Miele M, D'Agostini C, Pica F, Grelli S, Paci M, Mastino A, Sinibaldi Vallebona P, Garaci E, Tomino C

Abstract
BACKGROUND: Thymosin alpha 1 (Tα1) is a well-recognized immune response modulator in a wide range of disorders, particularly infections and cancer. The bioinformatic analysis of public databases allows drug repositioning, predicting a new potential area of clinical intervention. We aimed to decipher the cellular network induced by Tα1 treatment to confirm present use and identify new potential clinical applications.
RESEARCH DESIGN AND METHODS: We used the transcriptional profile of human peripheral blood mononuclear cells treated in vitro with Tα1 to perform the enrichment network analysis by the Metascape online tools and the disease enrichment analysis by the DAVID online tool.
RESULTS: Networked cellular responses reflected Tα1 regulated biological processes including immune and metabolic responses, response to compounds and oxidative stress, ion homeostasis, peroxisome biogenesis and drug metabolic process. Beyond cancer and infections, the analysis evidenced the association with disorders such as kidney chronic failure, diabetes, cardiovascular, chronic respiratory, neuropsychiatric, neurodegenerative and autoimmune diseases.
CONCLUSIONS: In addition to the known ability to promote immune response pathways, the network enrichment analysis demonstrated that Tα1 regulates cellular metabolic processes and oxidative stress response. Notable, the analysis highlighted the association with several diseases, suggesting new translational implication of Tα1 treatment in pathological conditions unexpected until now.

PMID: 30063863 [PubMed - in process]

A Small-molecule Kinase Inhibitor, CEP-1347, Inhibits Survivin Expression and Sensitizes Ovarian Cancer Stem Cells to Paclitaxel.

Anticancer Res. 2018 Aug;38(8):4535-4542

Authors: Togashi K, Okada M, Yamamoto M, Suzuki S, Sanomachi T, Seino S, Yamashita H, Kitanaka C

Abstract
BACKGROUND: Chemoresistance of cancer stem cells (CSCs) is considered a major cause of post-treatment recurrence that negatively impacts the prognosis of patients with ovarian cancer.
MATERIALS AND METHODS: Using CSCs derived from two different ovarian cancer cell lines, we searched for molecules implicated in the chemoresistance of ovarian CSCs and also drugs with which to target those molecules.
RESULTS: Knockdown of survivin overexpressed in ovarian CSCs resulted in increased sensitivity to paclitaxel. Treatment at clinically relevant concentrations with CEP-1347, a mixed lineage kinase inhibitor with a known safety profile in humans, reduced survivin expression in ovarian CSCs and sensitized them to paclitaxel.
CONCLUSION: Survivin overexpression plays a key role in the chemoresistance of ovarian CSCs. Introduction of CEP-1347, which targets survivin expression in ovarian CSCs, as a chemosensitizer for conventional ovarian cancer chemotherapy may serve as a rational and feasible approach for better management of ovarian cancer.

PMID: 30061219 [PubMed - in process]

Identification of potential anti-hepatitis C virus agents targeting non structural protein 5B using computational techniques.

J Cell Biochem. 2018 Jul 30;:

Authors: Polamreddy P, Vishwakarma V, Saxena P

Abstract
Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA-dependent RNA polymerase that plays a key role in HCV replication, and, hence, NS5B is an attractive target for hepatitis C drug discovery. Hepatitis C is a chronic liver disease affecting the global population significantly. Many NS5B inhibitors targeting active site were launched in recent years, however, still there exists a pressing need for cost-effective therapies with pan genotypic activity and therapies targeting niche HCV population with comorbities and resistant to earlier therapies. The objective of the current study is to identify potential anti-HCV agents from FDA approved drugs that are already in the market for a different disease-Drug repurposing approach. A combination of computational chemistry and computational biology techniques was used to discover potential therapies for hepatitis C targeting the NS5B Thumb I allosteric site. Computational chemistry analysis emphasized the fact that fluvastatin, a lipid lowering agent, and olopatadine, an antihistamine, exhibited good binding affinity to NS5B. In addition, gene set enrichment analysis brought to light the significant overlap between disease characteristic features and the mechanism of action of fluvastatin and olopatadine. The current study concludes the potentially beneficial use of fluvastatin in niche hepatitis C patient population suffering from nonalcoholic fatty liver diseases.

PMID: 30058078 [PubMed - as supplied by publisher]

Drug repurposing of quinine as antiviral against dengue virus infection.

Virus Res. 2018 Jul 25;:

Authors: Malakar S, Sreelatha L, Dechtawewat T, Noisakran S, Yenchitsomanus PT, Chu JJH, Limjindaporn T

Abstract
Dengue virus (DENV) disease outbreaks continue to develop across the globe with significant associated mortality and economic burden, yet no treatment has been approved to combat this virus. In an attempt to identify novel drug candidates as therapeutics for DENV infection, we evaluated four US Food and Drug Administration (FDA) approved drugs including aminolevullic acid, azelaic acid, mitoxantrone hydrochloride, and quinine sulfate, and tested their ability to inhibit DENV replication using focus-forming unit assay to quantify virus production. Of the four investigated compounds, quinine was found to have the most pronounced anti-DENV activity. Quinine inhibited DENV production of DENV by about 80% compared to untreated controls, while the other three drugs decreased virus production by only about 50%. Moreover, quinine inhibited DENV production of all four serotypes of DENV. Reduction in virus production was documented in three different cell lines of human origin. Quinine significantly inhibited DENV replication by reducing DENV RNA and viral protein synthesis in a dose-dependent manner. In addition, quinine ameliorated expression of genes related to innate immune response. These findings suggest the efficacy of quinine for stimulating antiviral genes to reduce DENV replication. The antiviral activity of quinine observed in this study may have applicability in the development of new drug therapies against DENV.

PMID: 30055216 [PubMed - as supplied by publisher]

A drug-repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6-thioguanine as an effective therapeutic agent for TPMT-low cancer cells.

Mol Oncol. 2018 Jul 28;:

Authors: Kim I, Choi YS, Song JH, Choi EA, Park S, Lee EJ, Rhee JK, Kim SC, Chang S

Abstract
Pancreatic cancer is one of the most difficult cancers to cure, due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive-compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose-dependent analysis revealed three compounds with a tumor cell-specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6-thioguanine (6-TG) showed IC50 of 0.39-1.13μM toward PDAC cells, but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6-TG. Lastly, we used a patient-derived xenograft model to confirm that 6-TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6-TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.

PMID: 30055072 [PubMed - as supplied by publisher]

Integrative omics analyses broaden treatment targets in human cancer.

Genome Med. 2018 Jul 27;10(1):60

Authors: Sengupta S, Sun SQ, Huang KL, Oh C, Bailey MH, Varghese R, Wyczalkowski MA, Ning J, Tripathi P, McMichael JF, Johnson KJ, Kandoth C, Welch J, Ma C, Wendl MC, Payne SH, Fenyö D, Townsend RR, Dipersio JF, Chen F, Ding L

Abstract
BACKGROUND: Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers.
METHODS: To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.
RESULTS: Within the pan-cancer cohort of 6570 tumors, we found that 3% are druggable based on FDA-approved drug-mutation interactions in specific cancer types. However, mRNA/phosphoprotein/protein expression outliers and drug repurposing across cancer types suggest potential druggability in up to 16% of tumors. The percentage of potential drug-associated tumors can increase to 48% if we consider preclinical evidence. Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively. We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool. Finally, analysis of a large-scale drug screening dataset lent further evidence supporting repurposing of drugs across cancer types and the use of expression outliers for inferring druggability.
CONCLUSIONS: Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.

PMID: 30053901 [PubMed - in process]

Emerging roles of Myc in stem cell biology and novel tumor therapies.

J Exp Clin Cancer Res. 2018 Jul 27;37(1):173

Authors: Yoshida GJ

Abstract
The pathophysiological roles and the therapeutic potentials of Myc family are reviewed in this article. The physiological functions and molecular machineries in stem cells, including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, are clearly described. The c-Myc/Max complex inhibits the ectopic differentiation of both types of artificial stem cells. Whereas c-Myc plays a fundamental role as a "double-edged sword" promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression. Furthermore, given the therapeutic resistance of neuroendocrine tumors such as small-cell lung cancer and neuroblastoma, the roles of N-Myc in difficult-to-treat tumors are discussed. N-Myc-driven neuroendocrine tumors tend to highly express NEUROD1, thereby leading to the enhanced metastatic potential. Importantly enough, accumulating evidence strongly suggests that c-Myc can be a promising therapeutic target molecule among Myc family in terms of the biological characteristics of cancer stem-like cells (CSCs). The presence of CSCs leads to the intra-tumoral heterogeneity, which is mainly responsible for the therapeutic resistance. Mechanistically, it has been shown that Myc-induced epigenetic reprogramming enhances the CSC phenotypes. In this review article, the author describes two major therapeutic strategies of CSCs by targeting c-Myc; Firstly, Myc-dependent metabolic reprogramming is closely related to CD44 variant-dependent redox stress regulation in CSCs. It has been shown that c-Myc increases NADPH production via enhanced glutaminolysis with a finely-regulated mechanism. Secondly, the dormancy of CSCs due to FBW7-depedent c-Myc degradation pathway is also responsible for the therapeutic resistance to the conventional anti-tumor agents, the action points of which are largely dependent on the operation of the cell cycle. That is why the loss-of-functional mutations of FBW7 gene are expected to trigger "awakening" of dormant CSCs in the niche with c-Myc up-regulation. Collectively, although the further research is warranted to develop the effective anti-tumor therapeutic strategy targeting Myc family, we cancer researchers should always catch up with the current advances in the complex functions of Myc family in highly-malignant and heterogeneous tumor cells to realize the precision medicine.

PMID: 30053872 [PubMed - in process]

Structural Basis for the Hepatoprotective Effects of Antihypertensive 1,4-Dihydropyridine Drugs.

Biochim Biophys Acta. 2018 Jul 23;:

Authors: Wei Y, Lu Y, Zhu Y, Zheng W, Guo F, Yao B, Xu S, Wang Y, Jin L, Li Y

Abstract
BACKGROUND: The 1,4-dihydropyridines (DHPs) are one of the most frequently prescribed classes of antihypertensive monotherapeutic agents worldwide. In addition to treating hypertension, DHPs also exert other beneficial effects, including hepatoprotective effects. However, the mechanism underlying the hepatoprotection remains unclear.
METHODS: Biochemical AlphaScreen and cell-based reporter assays were employed to detect the activities of DHPs towards FXR. A crystallographic analysis was adopted to study the binding modes of four DHPs in complex with FXR. Acetaminophen (APAP)-treated wild-type and FXR knockout mice were used to investigate the functional dependence of the effects of the selected DHPs on FXR.
RESULTS: A series of DHPs were uncovered as FXR ligands with different activities for FXR, suggesting FXR might serve as an alternative drug target for DHPs. The structural analysis illustrated the specific three-blade propeller binding modes of four DHPs to FXR and explained the detailed mechanisms by which DHPs bind to and are recognized by FXR. The results in mice demonstrated that cilnidipine protected the liver from APAP-induced injury in an FXR-dependent manner.
CONCLUSIONS: This study reports the crystal structures of FXR in complex with four DHPs, and confirms that DHPs exert hepatoprotection by targeting FXR.
GENERAL SIGNIFICANCE: Our research not only reveals valuable insight for the design and development of next-generation Ca2+ blocker drugs to provide safer and more effective treatments for cardiovascular disorders but also provides a novel and safe structural template for the development of drugs targeting FXR. Moreover, DHPs might be potentially repurposed to treat FXR-mediated diseases other than hypertension.

PMID: 30048741 [PubMed - as supplied by publisher]

Drug discovery for the treatment of substance use disorders: novel targets, repurposing, and the need for new paradigms.

Curr Opin Pharmacol. 2017 08;35:120-124

Authors: Chiamulera C, Padovani L, Corsi M

Abstract
Drug addiction treatment medications available nowadays are limited in both efficacy and number. The increased understanding of drug addiction circuitries leads the scientific community to look for better molecules and targets for detoxification and relapse prevention. This review focus on known targets (e.g., metabotropic glutamate receptor 5 and GABAB receptor) and on novel potential treatment acting on oxytocin system, which interacts with diverse neurotransmitters, has proved successful in both preclinical and clinical studies on ethanol, cocaine and methamphetamine. A crucial issue is the identification of new investigational paradigms, which may help to predict treatment efficacy and improve effectiveness.

PMID: 28874314 [PubMed - indexed for MEDLINE]

Considerations in the repurposing of mefloquine for prevention and treatment of osteoporosis.

Bone. 2018 Sep;114:304-305

Authors: Nevin RL

PMID: 30037669 [PubMed - in process]

Propranolol and breast cancer-a work in progress.

Ecancermedicalscience. 2018;12:ed82

Authors: Pantziarka P, Bryan BA, Crispino S, Dickerson EB

Abstract
The non-selective beta-blocker propranolol is a leading candidate for repurposing as a novel anti-cancer agent. Emerging evidence, including human data, suggests that there are multiple mechanisms of action particularly relevant to breast cancer. This editorial reviews a number of recent studies that show it has anti-metastatic activity that warrants clinical investigation, including investigation as a potential perioperative therapy in breast cancer.

PMID: 30034523 [PubMed]

Master Regulators Connectivity Map: A Transcription Factors-Centered Approach to Drug Repositioning.

Front Pharmacol. 2018;9:697

Authors: De Bastiani MA, Pfaffenseller B, Klamt F

Abstract
Drug discovery is a very expensive and time-consuming endeavor. Fortunately, recent omics technologies and Systems Biology approaches introduced interesting new tools to achieve this task, facilitating the repurposing of already known drugs to new therapeutic assignments using gene expression data and bioinformatics. The inherent role of transcription factors in gene expression modulation makes them strong candidates for master regulators of phenotypic transitions. However, transcription factors expression itself usually does not reflect its activity changes due to post-transcriptional modifications and other complications. In this aspect, the use of high-throughput transcriptomic data may be employed to infer transcription factors-targets interactions and assess their activity through co-expression networks, which can be further used to search for drugs capable of reverting the gene expression profile of pathological phenotypes employing the connectivity maps paradigm. Following this idea, we argue that a module-oriented connectivity map approach using transcription factors-centered networks would aid the query for new repositioning candidates. Through a brief case study, we explored this idea in bipolar disorder, retrieving known drugs used in the usual clinical scenario as well as new candidates with potential therapeutic application in this disease. Indeed, the results of the case study indicate just how promising our approach may be to drug repositioning.

PMID: 30034338 [PubMed]

Current treatment options and the role of peptides as potential therapeutic components for Middle East Respiratory Syndrome (MERS): A review.

J Infect Public Health. 2018 Jan - Feb;11(1):9-17

Authors: Mustafa S, Balkhy H, Gabere MN

Abstract
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a highly pathogenic respiratory virus with mechanisms that may be driven by innate immune responses. Despite the effort of scientific studies related to this virus, Middle East Respiratory Syndrome (MERS) is still a public health concern. MERS-CoV infection has a high mortality rate, and to date, no therapeutic or vaccine has been discovered, that is effective in treating or preventing the disease. In this review, we summarize our understanding of the molecular and biological events of compounds acting as MERS-CoV inhibitors, the outcomes of existing therapeutic options and the various drugs undergoing clinical trials. Currently, several therapeutic options have been employed, such as convalescent plasma (CP), intravenous immunoglobulin (IVIG), monoclonal antibodies and repurposing of existing clinically approved drugs. However, these therapeutic options have drawbacks, thus the need for an alternative approach. The requirement for effective therapeutic treatment has brought the necessity for additional MERS treatments. We suggest that antimicrobial peptides (AMPs) may be used as alternative therapeutic agents against MERS-CoV infection. In addition, we propose the feasibility of developing effective agents by repurposing the existing and clinically approved anti-coronavirus and anti-viral peptide drugs.

PMID: 28864360 [PubMed - indexed for MEDLINE]

The positive inotropic agent DPI-201106 selectively reverses ABCB1-mediated multidrug resistance in cancer cell lines.

Cancer Lett. 2018 Jul 18;:

Authors: Hsiao SH, Murakami M, Yeh N, Li YQ, Hung TH, Wu YS, Ambudkar SV, Wu CP

Abstract
The overexpression of ABCB1 in cancer cells is a major factor contributing to the development of multidrug resistance (MDR) and treatment failure in cancer patients. Therefore, re-sensitization of MDR cancer cells to anticancer drugs remains an important aspect in chemotherapy. The progress in developing clinically applicable synthetic inhibitors of ABCB1 has been slow, mostly due to complications associated with intrinsic toxicities and unforeseen drug-drug interactions. Here, we explored the drug-repositioning approach for cancer therapy by targeting ABCB1-mediated MDR in human cancer cells. We found that DPI-201106, a positive inotropic agent, selectively inhibits the drug efflux function of ABCB1, and in doing so, re-sensitizes ABCB1-overexpressing MDR cancer cells to conventional anticancer drugs. Furthermore, the ATPase activity of ABCB1 and docking analysis of DPI-201106 in the drug-binding pocket of ABCB1 were determined to confirm the interaction between DPI-201106 and ABCB1 protein. In summary, we revealed an additional action and a potential clinical application of DPI-201106 to reverse ABCB1-mediated MDR in human cancer cells, which may be beneficial for cancer patients who have developed multidrug resistance and no longer respond to conventional chemotherapy, and should be further investigated.

PMID: 30031116 [PubMed - as supplied by publisher]

Network Based Drug Discovery: Coupling Network Pharmacology with Phenotypic Screening for Neuronal Excitability.

J Mol Biol. 2018 Jul 17;:

Authors: Sidders B, Karlsson A, Kitching L, Torella R, Karila P, Phelan A

Abstract
Diseases such as chronic pain with complex aetiologies are unlikely to respond to single, target specific therapeutics but rather require intervention at multiple points within a perturbed disease system. Such approaches are being enabled by the rise of computational methods to identify key points of intervention and by new screening techniques that focus on a relevant condition or phenotype, rather than a specific target. Here we apply an in silico network pharmacology approach to identify small molecule compounds with the potential to selectively disrupt the structure of a chronic pain specific disease network, which we validate using a novel phenotypic screen that recapitulates key aspects of neuronal and pain biology by measuring changes in neuronal excitability in native sensory neurons. The combination of network pharmacology with a phenotypic screen is a powerful approach; we show that hit rates increase from 26% to 42%. This represents a rational approach to the discovery of compounds with a poly-pharmacology based therapeutic value, which will be vital for the discovery of treatments for complex disease.

PMID: 30030026 [PubMed - as supplied by publisher]

Recent Advances in Drug Repurposing for Parkinson's Disease.

Curr Med Chem. 2018 Jul 19;:

Authors: Chen X, Gumina G, Virga KG

Abstract
As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson's disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progress. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and time-efficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson's disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson's disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson's disease will be discussed.

PMID: 30027839 [PubMed - as supplied by publisher]

Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques.

ACS Omega. 2018 Mar 31;3(3):2564-2568

Authors: Shave S, McGuire K, Pham NT, Mole DJ, Webster SP, Auer M

Abstract
In this study, we apply a battery of molecular similarity techniques to known inhibitors of kynurenine 3-monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing.

PMID: 30023839 [PubMed]