Exploration of interaction scoring criteria in the CANDO platform.

BMC Res Notes. 2019 Jun 07;12(1):318

Authors: Falls Z, Mangione W, Schuler J, Samudrala R

Abstract
OBJECTIVE: Ascertain the optimal interaction scoring criteria for the Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun drug repurposing to improve benchmarking performance, thereby enabling more accurate prediction of novel therapeutic drug-indication pairs.
RESULTS: We have investigated and enhanced the interaction scoring criteria in the bioinformatic docking protocol in the newest version of our platform (v1.5), with the best performing interaction scoring criterion yielding increased benchmarking accuracies from 11.7% in v1 to 12.8% in v1.5 at the top10 cutoff (the most stringent one) and correspondingly from 24.9 to 31.2% at the top100 cutoff.

PMID: 31174591 [PubMed - in process]

Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis.

Int Immunopharmacol. 2019 Jun 04;73:482-490

Authors: Lee SJ, Gharbi A, You JS, Han HD, Kang TH, Hong SH, Park WS, Jung ID, Park YM

Abstract
There is currently no specific drug for the treatment of sepsis and antibiotic administration is considered the best option, despite numerous issues. Therefore, the development of drugs to control the pathogen-induced inflammatory responses associated with sepsis is essential. To address this, our study examined the transcriptomes of lipopolysaccharide (LPS)-induced dendritic cells (DCs), identifying TANK-binding kinase1 (Tbk1) as a key factor involved in the inflammatory response. These data suggested drug repositioning of the Tbk1 inhibitor CYT387, currently used for the treatment of myelofibrosis and some cancers, as a candidate for regulating the LPS-induced inflammatory response. CYT387 also inhibited pro-inflammatory cytokine and surface molecule expression by mature DCs after LPS exposure. These effects correlated with both Akt phosphorylation and IκBα degradation. Finally, CYT387 demonstrated therapeutic effects in LPS-induced endotoxemia and Escherichia coli K1-induced mouse models of sepsis and decreased the expression of pro-inflammatory cytokines. In conclusion, our study suggests that drug repositioning of CYT387 may serve as a potential therapeutic for sepsis.

PMID: 31173970 [PubMed - as supplied by publisher]

Aripiprazole repurposed as an inhibitor of biofilm formation, and sterol biosynthesis in multi-drug resistant Candida albicans.

Int J Antimicrob Agents. 2019 Jun 04;:

Authors: Rajasekharan SK, Lee JH, Lee J

Abstract
Drug repurposing is an anticipative chemotherapeutic strategy that serves to accentuate the inadequacy of antifungal drugs. The study identifies an antipsychotic drug, aripiprazole, as a biofilm and hyphal inhibitor of Candida albicans. Microtitre plate biofilm inhibition, metabolic activity, and hyphal inhibitory assays were used initially to assess the potency of aripiprazole, while assays like filipin staining, reactive oxygen species staining, cAMP rescue, propidium iodide staining, computational studies, and qRT-PCR assays were used to elucidate its mode of action. The study revealed aripiprazole functioned in a manner similar to standard azoles, especially the imidazole ketoconazole, by inhibiting pseudohyphal formations during the early stages of hyphal development. The action of aripiprazole on C. albicans was dose-dependent and it exhibited varied action mechanisms at low and high dosages. At low dosage, aripiprazole outperformed ketoconazole in terms of inhibiting biofilm formation, hyphal filamentations, and yeast flocculation whereas at higher dosage it mimicked ketoconazole. In conclusion, the study illustrates the anti-candidal potential and mechanistic activities of aripiprazole, and suggests the future use of this drug as an anti-biofilm agent.

PMID: 31173863 [PubMed - as supplied by publisher]

Can we teach old drugs new tricks? - Repurposing of neuropharmacological drugs for inflammatory skin diseases.

Exp Dermatol. 2019 Jun 07;:

Authors: Abels C, Soeberdt M

Abstract
Despite the "hype" for monoclonal antibodies, the so called biologics, which added significant value to the therapeutic armamentarium of dermatologists and improved the life of many patients, but may exhibit significant adverse effects, the vast majority of dermatological patients suffering from Atopic Dermatitis or Psoriasis is still treated topically. Thus, there is a huge need for locally applied, locally acting drugs for inflammatory skin diseases with better risk-benefit profiles compared to topical corticosteroids or calcineurin inhibitors. Drug repositioning is a complex process, but offers advantages, in particular for indications with lower revenues. In this viewpoint the neuroendocrine system of the skin is described as an attractive drug target because it contributes significantly to neutralizing external noxious agents prior to inducing immune or vascular changes leading to the clinical signs of skin inflammation, e.g. itch and erythema. In addition, epidermis and dermis are accessible for topically applied products which may act locally without pharmacodynamically relevant systemic exposure limiting adverse events. Moreover, since numerous drugs have been evaluated for various CNS diseases, some failed and some approved, this resource should be exploited for repurposing as anti-inflammatory drugs for topical application, e.g. cannabidiol, fingolimod or asimadoline. Finally, a screening algorithm is shared which gives direct evidence of links between drug and inflammatory skin diseases. This article is protected by copyright. All rights reserved.

PMID: 31173654 [PubMed - as supplied by publisher]

vulcanSpot: a tool to prioritize therapeutic vulnerabilities in cancer.

Bioinformatics. 2019 Jun 07;:

Authors: Perales-Patón J, Domenico TD, Fustero-Torre C, Piñeiro-Yáñez E, Carretero-Puche C, Tejero H, Valencia A, Gómez-López G, Al-Shahrour F

Abstract
MOTIVATION: Genetic alterations lead to tumor progression and cell survival but also uncover cancer-specific vulnerabilities on gene dependencies that can be therapeutically exploited.
RESULTS: vulcanSpot is a novel computational approach implemented to expand the therapeutic options in cancer beyond known-driver genes unlocking alternative ways to target undruggable genes. The method integrates genome-wide information provided by massive screening experiments to detect genetic vulnerabilities associated to tumors. Then, vulcanSpot prioritizes drugs to target cancer-specific gene dependencies using a weighted scoring system based on well known drug-gene relationships and drug repositioning strategies.
AVAILABILITY: http://www.vulcanspot.org.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 31173067 [PubMed - as supplied by publisher]

Illuminating the Onco-GPCRome: Novel G protein-coupled receptor-driven oncocrine networks and targets for cancer immunotherapy.

J Biol Chem. 2019 Jun 05;:

Authors: Wu V, Yeerna H, Nohata N, Chiou J, Harismendy O, Raimondi F, Inoue A, Russell RB, Tamayo P, Gutkind JS

Abstract
G protein-coupled receptors (GPCRs) are the largest gene family of cell membrane-associated molecules mediating signal transmission, and their involvement in key physiological functions is well established. The ability of GPCRs to regulate a vast array of fundamental biological processes, such as cardiovascular functions, immune responses, hormone and enzyme release from endocrine and exocrine glands, neurotransmission, and sensory perception (e.g. vision, odor, and taste) is largely due to the diversity of these receptors and the layers of their downstream signaling circuits. Dysregulated expression and aberrant functions of GPCRs have been linked to some of the most prevalent human diseases, which renders GPCRs one of the top targets for pharmaceutical drug development. However, the study of the role of GPCRs in tumor biology has only just begun to make headway. Recent studies have shown that GPCRs can contribute to the many facets of tumorigenesis, including proliferation, survival, angiogenesis, invasion, metastasis, therapy resistance, and immune evasion. Indeed, GPCRs are widely dysregulated in cancer and yet are underexploited in oncology. We present here a comprehensive analysis of GPCR gene expression, copy number variation, and mutational signatures in  33 cancer types. We also highlight the emerging role of GPCRs as part of oncocrine networks promoting tumor growth, dissemination, and immune evasion, and stress the potential benefits of targeting GPCRs and their signaling circuits in the new era of precision medicine and cancer immunotherapies.

PMID: 31171722 [PubMed - as supplied by publisher]

Drug repurposing in neurological diseases: an integrated approach to reduce trial and error.

J Neurol Neurosurg Psychiatry. 2019 Jun 06;:

Authors: Clout AE, Della Pasqua O, Hanna MG, Orlu M, Pitceathly RDS

Abstract
Identifying effective disease-modifying therapies for neurological diseases remains an important challenge in drug discovery and development. Drug repurposing attempts to determine new indications for pre-existing compounds and represents a major opportunity to address this clinically unmet need. It is potentially more cost-effective and time-efficient than de novo drug development and has yielded notable successes in neurological disorders. However, across all medical disciplines, only 30% of repurposed drugs, and 10% of novel candidate molecules, gain market approval. One potentially significant contributor towards this limited success rate is an incomplete knowledge of the exposure-response relationships for the compounds of interest, and how these relate to the new indication, prior to commencing a new trial. We provide an overview of the current approach to early-stage drug repurposing and consider the issues contributing to inconclusive, or possibly falsely negative, Phase II and III trial outcomes in neurological diseases by highlighting examples that illustrate the limitations of empirical evidence generation without a strong scientific basis for the dose rationale. We conclude with a framework suggesting a translational, iterative approach, that integrates pharmacological, pharmaceutical and clinical expertise, towards preclinical and early clinical drug development. This ensures appropriate dosing regimen, route of administration and/or formulation are selected for the new indication before their evaluation in prospective clinical trials.

PMID: 31171583 [PubMed - as supplied by publisher]

Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

JCI Insight. 2019 Jun 06;4(11):

Authors: Hansen J, Galatioto J, Caescu CI, Arnaud P, Calizo RC, Spronck B, Murtada SI, Borkar R, Weinberg A, Azeloglu EU, Bintanel-Morcillo M, Gallo JM, Humphrey JD, Jondeau G, Boileau C, Ramirez F, Iyengar R

Abstract
Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.

PMID: 31167969 [PubMed - in process]

Progress of Antimicrobial Discovery Against the Major Cariogenic Pathogen Streptococcus mutans.

Curr Issues Mol Biol. 2019 Jun 05;32:601-644

Authors: Cui T, Luo W, Xu L, Yang B, Zhao W, Cang H

Abstract
Dental caries, also known as tooth decay, or cavities, remains a global public health issue. Streptococcus mutans is considered the most significant contributor to dental caries. Its cariogenicity typically depends on its unique metabolic activity and lifestyle, including acid production, acid tolerance and biofilm formation. Currently used anti-caries therapies, such as fluoride and chlorhexidine, are characterized by side-effects and drug resistance. Therefore, the development of alternative inhibitors against S. mutans growth is urgently needed. In the last decade, a larger number of natural products and their derivatives from plants, marine organisms and microorganisms were studied to evaluate their antibacterial activity against S. mutans. In addition, drug-repositioning base screening and target based high-throughput screening were employed, resulting in inspiring progresses in recent years. In this review, we summarized the available evidences regarding the inhibition of S. mutans growth. We focus on the sources, structures and potential mechanism of action of these inhibitors. Beside small molecular compounds, we also considered antibacterial peptides and protein inhibitors developed in this field.

PMID: 31166181 [PubMed - as supplied by publisher]

High Efficiency Drug Repurposing Design for New Antifungal Agents.

Methods Protoc. 2019 Apr 17;2(2):

Authors: Kim JH, Chan KL, Cheng LW, Tell LA, Byrne BA, Clothier K, Land KM

Abstract
Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated "chemosensitization" as a method to improve the efficiency of antifungal drug repurposing, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent chemosensitizers to enhance antifungal activity of the repurposed drug bithionol. Of note, inclusion of fungal mutants, such as antioxidant mutants, could also facilitate drug repurposing efficiency, which is reflected in the enhancement of antifungal efficacy of bithionol. Bithionol overcame antifungal (viz., fludioxonil) tolerance of the antioxidant mutants of the human/animal pathogen Aspergillus fumigatus. Altogether, our strategy can lead to the development of a high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abates drug or fungicide resistance.

PMID: 31164611 [PubMed]

Mining heterogeneous network for drug repositioning using phenotypic information extracted from social media and pharmaceutical databases.

Artif Intell Med. 2019 May;96:80-92

Authors: Yang CC, Zhao M

Abstract
Drug repositioning has drawn significant attention for drug development in pharmaceutical research and industry, because of its advantages in cost and time compared with the de novo drug development. The availability of biomedical databases and online health-related information, as well as the high-performance computing, empowers the development of computational drug repositioning methods. In this work, we developed a systematic approach that identifies repositioning drugs based on heterogeneous network mining using both pharmaceutical databases (PharmGKB and SIDER) and online health community (MedHelp). By utilizing adverse drug reactions (ADRs) as the intermediate, we constructed a heterogeneous health network containing drugs, diseases, and ADRs, and developed path-based heterogeneous network mining approaches for drug repositioning. Additionally, we investigated on how the data sources affect the performance on drug repositioning. Experiment results showed that combining both PharmKGB and MedHelp identified 479 repositioning drugs, which are more than the repositioning drugs discovered by other alternatives. In addition, 31% of the 479 of the discovered repositioning drugs were supported by evidence from PubMed.

PMID: 31164213 [PubMed - in process]

Chemical inhibitors of Candida albicans hyphal morphogenesis target endocytosis.

Sci Rep. 2017 07 18;7(1):5692

Authors: Bar-Yosef H, Vivanco Gonzalez N, Ben-Aroya S, Kron SJ, Kornitzer D

Abstract
Candida albicans is an opportunistic pathogen, typically found as a benign commensal yeast living on skin and mucosa, but poised to invade injured tissue to cause local infections. In debilitated and immunocompromised individuals, C. albicans may spread to cause life-threatening systemic infections. Upon contact with serum and at body temperature, C. albicans performs a regulated switch to filamentous morphology, characterized by emergence of a germ tube from the yeast cell followed by mold-like growth of branching hyphae. The ability to switch between growth morphologies is an important virulence factor of C. albicans. To identify compounds able to inhibit hyphal morphogenesis, we screened libraries of existing drugs for inhibition of the hyphal switch under stringent conditions. Several compounds that specifically inhibited hyphal morphogenesis were identified. Chemogenomic analysis suggested an interaction with the endocytic pathway, which was confirmed by direct measurement of fluid-phase endocytosis in the presence of these compounds. These results suggest that the activity of the endocytic pathway, which is known to be particularly important for hyphal growth, represents an effective target for hyphae-inhibiting drugs.

PMID: 28720834 [PubMed - indexed for MEDLINE]

T-Type voltage gated calcium channels: a target in breast cancer?

Breast Cancer Res Treat. 2019 Jan;173(1):11-21

Authors: Bhargava A, Saha S

Abstract
PURPOSE: The purpose of this review article is to discuss the potential of T-type voltage gated calcium channels (VGCCs) as drug targets in breast cancer. Breast cancer, attributable to the different molecular subtypes, has a crucial need for therapeutic strategies to counter the mortality rate. VGCCs play an important role in regulating cytosolic free calcium levels which regulate cellular processes like tumorigenesis and cancer progression. In the last decade, T-type VGCCs have been investigated in breast cancer proliferation. Calcium channel blockers, in general, have shown an anti-proliferative and cytotoxic effects. T-type VGCC antagonists have shown growth inhibition owing to the inhibition of CaV3.2 isoform. CaV3.1 isoform has been indicated as a tumour-suppressor gene candidate and is reported to support anti-proliferative and apoptotic activity in breast cancer. The distribution of T-type VGCC isoforms in different breast cancer molecular subtypes is diverse and needs to be further investigated. The role of T-type VGCCs in breast cancer migration, metastasis and more importantly in epithelial to mesenchymal transition (EMT) is yet to be elucidated. In addition, interlaced therapy, using a combination of chemotherapy drugs and T-type VGCC blockers, presents a promising therapeutic approach for breast cancer but more validation and clinical trials are needed. Also, for investigating the potential of T-type VGCC blocker therapy, there is a need for isoform-specific agonists/antagonists to define and discover roles of T-type VGCC specific isoforms.
CONCLUSION: Our article provides a review of the role of T-type VGCCs in breast cancer and also discusses future of the research in this area so that it can be ascertained whether there is any potential of T-type VGCCs as drug targets in breast cancer.

PMID: 30242580 [PubMed - indexed for MEDLINE]

Drug promiscuity: Exploring the polypharmacology potential of 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones as an inhibitor of the 'god father' of immune checkpoint.

Comput Biol Chem. 2019 May 22;80:433-440

Authors: Soremekun OS, Olotu FA, Agoni C, Soliman MES

Abstract
High production cost, instability, low tumor penetration are some of the shortcomings that have characterized and undermined the use of antibodies as a target for Cytotoxic T-lymphocytes associated protein 4 (CTLA-4). Design and discovery of small molecule inhibitors have therefore become a sine qua non in targeting immune proteins implicated in immune disorders. In this study, we utilized a drug repositioning approach to explore the characteristic feature of unrelated proteins to have similar binding sites and the promiscuity of drugs to repurpose an existing drug to target CTLA-4. CTLA-4 and Kallikrein-7 were found to have similar binding sites, we therefore used 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones (TDSO) which is an inhibitor of Kallikrein-7 as our lead compound. High throughput screening using TDSO as a lead compound resulted in 9 hits with ZINC04515726 and ZINC08985213 having the highest binding score. We went ahead to investigate the interaction of these compounds with CTLA-4 by conducting a molecular dynamic simulation. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) estimations revealed that TDSO had the highest binding energy value of -28.51Kcal/mol, with ZINC04515726 and ZINC08985213 having -23.76Kcal/mol and -21.03Kcal/mol respectively. The per-residue decomposition highlighted Tyr24, Ala25, Gly28, Ala30, Tyr53 and Asn72 as having significantly high electrostatic energy contributions and the main contributing residues to the binding of TDSO, ZINC04515726 and ZINC08985213 to Cytotoxic T lymphocytes CTLA-4. Summarily, from the results gathered, we proposed that TDSO can be an effective immune check point small molecule inhibitor against the suppression of T-cell activation, proliferation, and tumor cell eradication.

PMID: 31146119 [PubMed - as supplied by publisher]

Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery.

FASEB J. 2019 May 30;:fj201802603RR

Authors: Poser SW, Otto O, Arps-Forker C, Ge Y, Herbig M, Andree C, Gruetzmann K, Adasme MF, Stodolak S, Nikolakopoulou P, Park DM, Mcintyre A, Lesche M, Dahl A, Lennig P, Bornstein SR, Schroeck E, Klink B, Leker RR, Bickle M, Chrousos GP, Schroeder M, Cannistraci CV, Guck J, Androutsellis-Theotokis A

Abstract
Cancer cells can switch between signaling pathways to regulate growth under different conditions. In the tumor microenvironment, this likely helps them evade therapies that target specific pathways. We must identify all possible states and utilize them in drug screening programs. One such state is characterized by expression of the transcription factor Hairy and Enhancer of Split 3 (HES3) and sensitivity to HES3 knockdown, and it can be modeled in vitro. Here, we cultured 3 primary human brain cancer cell lines under 3 different culture conditions that maintain low, medium, and high HES3 expression and characterized gene regulation and mechanical phenotype in these states. We assessed gene expression regulation following HES3 knockdown in the HES3-high conditions. We then employed a commonly used human brain tumor cell line to screen Food and Drug Administration (FDA)-approved compounds that specifically target the HES3-high state. We report that cells from multiple patients behave similarly when placed under distinct culture conditions. We identified 37 FDA-approved compounds that specifically kill cancer cells in the high-HES3-expression conditions. Our work reveals a novel signaling state in cancer, biomarkers, a strategy to identify treatments against it, and a set of putative drugs for potential repurposing.-Poser, S. W., Otto, O., Arps-Forker, C., Ge, Y., Herbig, M., Andree, C., Gruetzmann, K., Adasme, M. F., Stodolak, S., Nikolakopoulou, P., Park, D. M., Mcintyre, A., Lesche, M., Dahl, A., Lennig, P., Bornstein, S. R., Schroeck, E., Klink, B., Leker, R. R., Bickle, M., Chrousos, G. P., Schroeder, M., Cannistraci, C. V., Guck, J., Androutsellis-Theotokis, A. Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery.

PMID: 31145643 [PubMed - as supplied by publisher]

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 2019/05/30

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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 2019/05/30

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.

miR-132 regulates the expression of synaptic proteins in APP/PS1 transgenic mice through C1q.

Eur J Histochem. 2019 May 03;63(2):

Authors: Xu N, Li AD, Ji LL, Ye Y, Wang ZY, Tong L

Abstract
Cognitive impairment in Alzheimer's disease (AD) is usually accompanied by synaptic loss in both the hippocampus and neocortex. In the early stage of AD, amyloid β-induced synapse changes is the main reason, while in the later stage, the accumulation of Tau protein promotes synapse degeneration as the key factor leading to dementia. MicroRNA (miRNA) is closely related to the expression changes of many AD-related genes. One of the most abundant brain-enriched miRNAs is miR-132, which has been shown to regulate both neuron morphogenesis and plasticity. It has been reported that miR-132 is significantly reduced in the brains of Alzheimer's patients. Genetic deletion of miR-132 in mice promotes Aβ deposition, leading to impaired memory and enhanced Tau pathology, but how the miRNA-mediated gene expression dysregulation contributes to AD pathology remains unclear. Here we found the possible downstream target of miR-132 by in silico analysis, namely C1q. C1q is the primary protein of classical complement cascade, which is highly expressed in the synaptic regions of the central nervous system in Alzheimer's patients. However, it is not clear whether miR-132 plays a role in AD through regulating C1q. To address this question, the APP/PS1 transgenic mice were transfected with miR-132 and given C1 inhibitors. Behavior tests were conducted to assess memory and cognitive abilities seven days after administration. In addition, we analyzed the expression of PSD95, Synapsin-1 and phosphorylated (p)-Synapsin. We found that the expression levels of the synaptic proteins treated with miR-132 or C1INH were significantly increased compared with the AD group. Further RT-qPCR result suggested that miR-132 might regulate C1q expression in AD.

PMID: 31060348 [PubMed - indexed for MEDLINE]

Exploiting machine learning for end-to-end drug discovery and development.

Nat Mater. 2019 05;18(5):435-441

Authors: Ekins S, Puhl AC, Zorn KM, Lane TR, Russo DP, Klein JJ, Hickey AJ, Clark AM

Abstract
A variety of machine learning methods such as naive Bayesian, support vector machines and more recently deep neural networks are demonstrating their utility for drug discovery and development. These leverage the generally bigger datasets created from high-throughput screening data and allow prediction of bioactivities for targets and molecular properties with increased levels of accuracy. We have only just begun to exploit the potential of these techniques but they may already be fundamentally changing the research process for identifying new molecules and/or repurposing old drugs. The integrated application of such machine learning models for end-to-end (E2E) application is broadly relevant and has considerable implications for developing future therapies and their targeting.

PMID: 31000803 [PubMed - indexed for MEDLINE]

Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.

Nat Commun. 2019 04 18;10(1):1817

Authors: Siddiqi FH, Menzies FM, Lopez A, Stamatakou E, Karabiyik C, Ureshino R, Ricketts T, Jimenez-Sanchez M, Esteban MA, Lai L, Tortorella MD, Luo Z, Liu H, Metzakopian E, Fernandes HJR, Bassett A, Karran E, Miller BL, Fleming A, Rubinsztein DC

Abstract
Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant α-synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration.

PMID: 31000720 [PubMed - indexed for MEDLINE]