Over 1,000 genetic loci influencing blood pressure with multiple systems and tissues implicated.

Hum Mol Genet. 2019 Aug 14;:

Authors: Cabrera CP, Ng FL, Nicholls HL, Gupta A, Barnes MR, Munroe PB, Caulfield MJ

Abstract
High blood pressure remains the major heritable and modifiable risk factor for cardiovascular disease (CVD). Persistent high blood pressure, or hypertension, is a complex trait with both genetic and environmental interactions. Despite swift advances in genomics, translating new discoveries to further our understanding of the underlying molecular mechanisms remains a challenge. More than 500 loci implicated in the regulation of blood pressure (BP) have been revealed by genome-wide association studies (GWAS) in 2018 alone, taking the total number of BP genetic loci to over 1,000. Even with the large number of loci now associated to BP, the genetic variance explained by all loci together remains low (~5.7%). These genetic associations have elucidated mechanisms and pathways regulating BP, highlighting potential new therapeutic and drug repurposing targets. A large proportion of the BP loci were discovered and reported simultaneously by multiple research groups, creating a knowledge gap, where the reported loci to date have not been investigated in a harmonious way. Here, we review the BP-associated genetic variants reported across GWAS studies and investigate their potential impact on the biological systems using in silico enrichment analyses for pathways, tissues, gene ontology and genetic pleiotropy.

PMID: 31411675 [PubMed - as supplied by publisher]

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Insights on the anticandidal activity of non-antifungal drugs.

J Mycol Med. 2019 Jul 27;:

Authors: Moraes DC, Ferreira-Pereira A

Abstract
The search for new antifungal strategies to overcome Candida infections is essential and a matter of public health, due to the high mortality associated to candidiasis, the increasing incidence of resistance to antifungals and the limited number of drugs available for treatment. Several approaches have been exploited in order to develop new antifungal strategies, e.g. the use of natural products, vaccines, and the combination of an antifungal drug to a non-antifungal substance. Nonetheless, issues related to pharmacokinetic parameters, toxicity and costs have been jeopardizing the discovery of new antifungal drugs. An alternative that could overcome these problems would be treating candidiasis with drugs that have been originally developed to treat other diseases. This strategy, known as drug repositioning or drug repurposing, could diminish the incidence of adverse effects and lower the cost of production, since several steps involved in drug discovery and development have already been accomplished. This review presents a set of known drugs that have been exploited as anticandidal agents, such as antidepressant agents, antiepileptic drugs, statins, among others. These substances affect the growth of Candida spp. in vitro, as well as virulence factors such as morphogenesis and biofilm formation. Moreover, some drugs are able to potentiate the anticandidal activity of known antifungal drugs. Drug repositioning appears as a remarkable alternative to increase the pharmacological arsenal against candidiasis, but further studies must be conducted in order to evaluate the real applicability of known drugs in the treatment of these infections.

PMID: 31399349 [PubMed - as supplied by publisher]

Maternal-to-zygotic transition as a potential target for niclosamide during early embryogenesis.

Toxicol Appl Pharmacol. 2019 Aug 06;:114699

Authors: Vliet SMF, Dasgupta S, Sparks NRL, Kirkwood JS, Vollaro A, Hur M, Zur Nieden NI, Volz DC

Abstract
Niclosamide is an antihelminthic drug used worldwide for the treatment of tapeworm infections. Recent drug repurposing screens have highlighted the broad bioactivity of niclosamide across diverse mechanisms of action. As a result, niclosamide is being evaluated for a range of alternative drug-repurposing 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, it is important to understand the mechanism of niclosamide toxicity during early stages of embryonic development. Previously, we showed that niclosamide induces a concentration-dependent delay in epiboly progression in the absence of effects on oxidative phosphorylation - a well-established target for niclosamide. Therefore, the overall objective of this study was to further examine the mechanism of niclosamide-induced epiboly delay during zebrafish embryogenesis. Based on this study, we found that (1) niclosamide exposure during early zebrafish embryogenesis resulted in a decrease in yolk sac integrity with a concomitant decrease in the presence of yolk sac actin networks and increase in cell size; (2) within whole embryos, niclosamide exposure did not alter non-polar metabolites and lipids, but significantly altered amino acids specific to aminoacyl-tRNA biosynthesis; (3) niclosamide significantly altered transcripts related to translation, transcription, and mRNA processing pathways; and (4) niclosamide did not significantly alter levels of rRNA and tRNA. Overall, our findings suggest that niclosamide may be causing a systemic delay in embryonic development by disrupting the translation of maternally-supplied mRNAs, an effect that may be mediated through disruption of aminoacyl-tRNA biosynthesis.

PMID: 31398420 [PubMed - as supplied by publisher]

Drug repurposing for the treatment of alveolar echinococcosis: in vitro and in vivo effects of silica nanoparticles modified with dichlorophen.

Parasitology. 2019 Aug 09;:1-36

Authors: Fabbri J, Pensel PE, Albani CM, Arce VB, Mártire DO, Elissondo MC

PMID: 31397256 [PubMed - as supplied by publisher]

Screening of Drug Repositioning Candidates for Castration Resistant Prostate Cancer.

Front Oncol. 2019;9:661

Authors: Kim IW, Kim JH, Oh JM

Abstract
Purpose: Most prostate cancers (PCs) initially respond to androgen deprivation therapy (ADT), but eventually many PC patients develop castration resistant PC (CRPC). Currently, available drugs that have been approved for the treatment of CRPC patients are limited. Computational drug repositioning methods using public databases represent a promising and efficient tool for discovering new uses for existing drugs. The purpose of the present study is to predict drug candidates that can treat CRPC using a computational method that integrates publicly available gene expression data of tumors from CRPC patients, drug-induced gene expression data and drug response activity data. Methods: Gene expression data from tumoral and normal or benign prostate tissue samples in CRPC patients were downloaded from the Gene Expression Omnibus (GEO) and differentially expressed genes (DEGs) in CRPC were determined with a meta-signature analysis by a metaDE R package. Additionally, drug activity data were downloaded from the ChEMBL database. Furthermore, the drug-induced gene expression data were downloaded from the LINCS database. The reversal relationship between the CRPC and drug gene expression signatures as the Reverse Gene Expression Scores (RGES) were computed. Drug candidates to treat CRPC were predicted using summarized scores (sRGES). Additionally, synergic effects of drug combinations were predicted with a Target Inhibition interaction using the Minimization and Maximization Averaging (TIMMA) algorithm. Results: The drug candidates of sorafenib, olaparib, elesclomol, tanespimycin, and ponatinib were predicted to be active for the treatment of CRPC. Meanwhile, CRPC-related genes, in this case MYL9, E2F2, APOE, and ZFP36, were identified as having gene expression data that can be reversed by these drugs. Additionally, lenalidomide in combination with pazopanib was predicted to be most potent for CRPC. Conclusion: These findings support the use of a computational reversal gene expression approach to identify new drug and drug combination candidates that can be used to treat CRPC.

PMID: 31396486 [PubMed]

Ketamine: A Neglected Therapy for Alzheimer Disease.

Front Aging Neurosci. 2019;11:186

Authors: Smalheiser NR

PMID: 31396078 [PubMed]

Survey of Similarity-based Prediction of Drug-protein Interactions.

Curr Med Chem. 2019 Aug 08;:

Authors: Wang C, Kurgan L

Abstract
Therapeutic activity of a significant majority of drugs is determined by their interactions with proteins. Databases of drug-protein interactions (DPIs) primarily focus on the therapeutic protein targets while the knowledge of the off-targets is fragmented and partial. One way to bridge this knowledge gap is to employ computational methods to predict protein targets for a given drug molecule, or interacting drugs for given protein targets. We survey a comprehensive set of 35 methods that were published in high-impact venues and that predict DPIs based on similarity between drugs and similarity between protein targets. We analyze the internal databases of known PDIs that these methods utilize to compute similarities, and investigate how they are linked to the 12 publicly available source databases. We discuss contents, impact and relationships between these internal and source databases, and well as the timeline of their releases and publications. The 35 predictors exploit and often combine three types of similarities that consider drug structures, drug profiles, and target sequences. We review the predictive architectures of these methods, their impact, and we explain how their internal DPIs databases are linked to the source databases. We also include a detailed timeline of the development of these predictors and discuss the underlying limitations of the current resources and predictive tools. Finally, we provide several recommendations concerning the future development of the related databases and methods.

PMID: 31393241 [PubMed - as supplied by publisher]

Comparison of Target Features for Predicting Drug-Target Interactions by Deep Neural Network Based on Large-Scale Drug-Induced Transcriptome Data.

Pharmaceutics. 2019 Aug 02;11(8):

Authors: Lee H, Kim W

Abstract
Uncovering drug-target interactions (DTIs) is pivotal to understand drug mode-of-action (MoA), avoid adverse drug reaction (ADR), and seek opportunities for drug repositioning (DR). For decades, in silico predictions for DTIs have largely depended on structural information of both targets and compounds, e.g., docking or ligand-based virtual screening. Recently, the application of deep neural network (DNN) is opening a new path to uncover novel DTIs for thousands of targets. One important question is which features for targets are most relevant to DTI prediction. As an early attempt to answer this question, we objectively compared three canonical target features extracted from: (i) the expression profiles by gene knockdown (GEPs); (ii) the protein-protein interaction network (PPI network); and (iii) the pathway membership (PM) of a target gene. For drug features, the large-scale drug-induced transcriptome dataset, or the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset was used. All these features are closely related to protein function or drug MoA, of which utility is only sparsely investigated. In particular, few studies have compared the three types of target features in DNN-based DTI prediction under the same evaluation scheme. Among the three target features, the PM and the PPI network show similar performances superior to GEPs. DNN models based on both features consistently outperformed other machine learning methods such as naïve Bayes, random forest, or logistic regression.

PMID: 31382356 [PubMed]

A computer-assisted discovery of novel potential anti-obesity compounds as selective carbonic anhydrase VA inhibitors.

Eur J Med Chem. 2019 Jul 27;181:111565

Authors: Costa G, Carta F, Ambrosio FA, Artese A, Ortuso F, Moraca F, Rocca R, Romeo I, Lupia A, Maruca A, Bagetta D, Catalano R, Vullo D, Alcaro S, Supuran CT

Abstract
The human Carbonic anhydrases (hCA) VA and VB play a key role in ureagenesis, gluconeogenesis, lipogenesis and in the metabolism regulation, thus representing highly popular drug targets. Albeit several hCA inhibitors have been designed and are currently in clinical use, serious drug interactions have been reported due to their poor selectivity. In this perspective, the drug repurposing approach could be a useful tool in order to investigate the drug promiscuity/polypharmacology profile. In this study, virtual screening techniques and in vitro assays were combined to identify novel selective hCA VA inhibitors from among around 94000 compounds. The docking analysis highlighted 12 promising best hits, biologically characterized in terms of their hCA VA inhibitory activity. Interestingly, among them, the anticancer agents fludarabine and lenvatinib and the antiepileptic rufinamide were able to selectively inhibit the enzyme activity in the micromolar range, while a pyrido-indole derivative, the homovanillic acid sulfate and the desacetyl metabolite of the antibacterial cephapirin in the nanomolar range.

PMID: 31387062 [PubMed - as supplied by publisher]

Repurposing of ginseng extract as topoisomerase I inhibitor based on the comparative analysis of gene expression patterns.

Phytochemistry. 2019 Aug;164:223-227

Authors: Byun MR, Kim CH, Lee HS, Choi JW, Lee SK

Abstract
Repositioning of plant extracts and chemical drugs can accelerate drug development. However, its success rate may depend on what the clue is for the repositioning. Recently, repositioning based on correction of unwarranted gene expression pattern has suggested the possibility of new drug development. Here, we designed a similar method for the repositioning of nutraceutical ginseng (Panax ginseng C.A.Mey.), which is one of the most validated natural therapeutic products for various diseases. We analyzed ginseng-induced gene expression profiles using the connectivity map algorithm, which is a database that connects diseases, chemical drugs, and gene expression. Ginseng was predicted to show the same effects as those of topoisomerase I inhibitors. In a subsequent in vitro assay, ginseng extract unwound coiled or supercoiled DNA, an effect comparable to that of the topoisomerase I inhibitor, camptothecin. Furthermore, ginseng extract induced synthetic lethality with suppression of the Werner syndrome gene. The collected data implicate ginseng as a candidate antitumor agent owing to its topoisomerase I inhibitory activity and further validate the usefulness of differentially expressed gene similarity-based repurposing of other natural products.

PMID: 31181353 [PubMed - indexed for MEDLINE]

Monensin may inhibit melanoma by regulating the selection between differentiation and stemness of melanoma stem cells.

PeerJ. 2019;7:e7354

Authors: Xin H, Li J, Zhang H, Li Y, Zeng S, Wang Z, Zhang Z, Deng F

Abstract
Melanoma is the most lethal cutaneous malignancy that threatens human lives. Poor sensitivity to chemotherapy drugs and the high rate of resistance are the bottlenecks of melanoma treatment. Thus, new chemotherapy drugs are needed. Drug repurposing is a safe, economical and timesaving way to explore new chemotherapy for diseases. Here, we investigated the possibility of repurposing the antibiotic monensin as an anti-melanoma agent. Using three human melanoma cells and two nomal human cell lines as cell models, we found that monensin is obviously toxic to human melanoma cells while safe to nomal human cells. It effectively inhibited cell proliferation and viability, while promoted apoptosis and differentiation of human melanoma cells in vitro. By establishment of an animal model of transplanted human melanoma in nude mice, we demonstrated that monensin suppressed the growth of xenografts in vivo. At the same time, we found that melanogenesis increased and the ability of sphere and cloning forming of melanoma decreased under the treatment of monensin. Further detection about differentiation and pluripotent regulations were executed. Our results suggest that monensin is a potent inhibitor of melanoma, and its anti-tumor mechanism may be through promoting the final differentiation of melanoma stem cells and inhibiting their stemness maintenance.

PMID: 31380151 [PubMed]

A New Use for an Old Drug: Carmofur Attenuates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Inhibition of FAAH and NAAA Activities.

Front Pharmacol. 2019;10:818

Authors: Wu K, Xiu Y, Zhou P, Qiu Y, Li Y

Abstract
Acute lung injury (ALI), characterized by a severe inflammatory process, is a complex syndrome that can lead to multisystem organ failure. Fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA) are two potential therapeutic targets for inflammation-related diseases. Herein, we identified carmofur, a 5-fluorouracil-releasing drug and clinically used as a chemotherapeutic agent, as a dual FAAH and NAAA inhibitor. In Raw264.7 macrophages, carmofur effectively reduced the mRNA expression of pro-inflammatory factors, including IL-1β, IL-6, iNOS, and TNF-α, and down-regulated signaling proteins of the nuclear transcription factor κB (NF-κB) pathway. Furthermore, carmofur significantly ameliorated the inflammatory responses and promoted resolution of pulmonary injury in lipopolysaccharide (LPS)-induced ALI mice. The pharmacological effects of carmofur were partially blocked by peroxisome proliferator-activated receptor-α (PPARα) antagonist MK886 and cannabinoid receptor 2 (CB2) antagonist SR144528, indicating that carmofur attenuated LPS-induced ALI in a PPARα- and CB2-dependent mechanism. Our study suggested that carmofur might be a novel therapeutic agent for ALI, and drug repurposing may provide us effective therapeutic strategies for ALI.

PMID: 31379583 [PubMed]

Combination Therapy with Disulfiram, Copper, and Doxorubicin for Osteosarcoma: In Vitro Support for a Novel Drug Repurposing Strategy.

Sarcoma. 2019;2019:1320201

Authors: Mandell JB, Lu F, Fisch M, Beumer JH, Guo J, Watters RJ, Weiss KR

Abstract
Although many cancer cells have significantly higher copper concentrations compared with normal cells and tissues, the role of copper in cancer biology and metastatic disease remains poorly understood. Here, we study the importance of copper in osteosarcoma, which frequently metastasizes to the lungs and is often chemoresistant. K12 and K7M2 are murine OS cells with differing metastatic phenotypes: K7M2 is highly metastatic, whereas K12 is much less so. Intracellular copper levels were determined using atomic absorption. Copper transporters were quantified by qPCR. Cytotoxicity of doxorubicin, disulfiram, and copper(II) chloride was assessed with a cell viability fluorescence stain. Additionally, K7M2 viable cell counts were determined by trypan blue exclusion staining after 72 hours of treatment. Copper levels were found to be significantly higher in K12 OS cells than in K7M2 cells. qPCR showed that K12 cells upregulate the copper influx pump CTR1 and downregulate the copper efflux pump ATP7A compared to K7M2 OS cells. Combination treatment of copper chloride (50 nM) with disulfiram (80 nM) was only cytotoxic to K12 cells. Triple treatment with doxorubicin, disulfiram, and copper displayed potent and durable cytotoxicity of highly metastatic K7M2 cells. We demonstrate here that murine OS cell lines differing in metastatic potential also vary in endogenous copper levels and regulation. Additionally, these differences in copper regulation may contribute to selective cytotoxicity of K12 cells by extremely low doses of copper-potentiated disulfiram. The combination of doxorubicin, disulfiram, and copper should be explored as a therapeutic strategy against OS metastases.

PMID: 31379466 [PubMed]

A Systematic Computational Analysis of Human Matrix Metalloproteinase 13 (MMP-13) Crystal Structures and Structure-based Identification of Prospective Drug Candidates as MMP-13 Inhibitors Repurposable for Osteoarthritis.

J Biomol Struct Dyn. 2019 Aug 05;:1-20

Authors: Satish Kumar K, Velayutham R, Roy KK

Abstract
Osteoarthritis (OA) is the most common form of arthritis with no available disease-modifying treatments, and is a major cause of disability. Matrix Metalloproteinase 13 (MMP-13) is vital for OA progression and thus, inhibition of MMP-13 is an effective strategy to treat OA. Since the past few decades, drug repurposing has gained substantial popularity worldwide as a time- and cost-effective approach to find new indications for the existing drugs. Therefore, more than 40 X-ray co-crystal structures of the human MMP-13 with bound inhibitors are investigated to gain the structural insights such as conserved direct-interactions with binding site residues, viz. Ala-238, Thr-245 and Thr-247. Afterwards, enrichment study using active and decoy set of ligands revealed three MMP-13 structures (PDB-IDs: 1XUC, 3WV1 and 5BPA) with optimal enrichment performance. Docking-based screening of existing drugs against the three crystal structures followed by binding free-energy calculation suggested drugs viz. eltrombopag, cilostazol and domperidone as potential MMP-13 inhibitors that need further experimental validation. These insights may serve as a potential starting point of further experimental validation and structure-based drug design/repurposing of MMP-13 inhibitors for the treatment of OA.

PMID: 31378153 [PubMed - as supplied by publisher]

Repurposing an inhibitor of ribosomal biogenesis with broad anti-fungal activity.

Sci Rep. 2017 12 05;7(1):17014

Authors: Sun N, Li D, Zhang Y, Killeen K, Groutas W, Calderone R

Abstract
The lack of new antifungal compounds with unique mechanisms of action is a concern for therapeutic management of patients. To identify inhibitors against human pathogenic fungi, we screened ~3000 compounds provided by the Developmental Therapeutics Program of NIH/NCI against a panel of pathogenic fungi including Candida species, Aspergillus fumigatus, and Cryptococcus neoformans. NSC319726 (a thiosemicarbazone) had broad antifungal activity in the range of 0.1-2.0 µg/ml and was also inhibitory to fluconazole-resistant isolates of Candida species. Synergy was demonstrated with NSC319726 and azoles, as well as caspofungin. The inhibitory concentration 50% (IC50) of NSC319726 was 35-800-fold higher than the Minimum Inhibitory Concentration 50% (MIC50 values), which indicates low compound toxicity to human cells in vitro. Transcriptome analysis of treated and untreated C. albicans using Gene Ontology (GO) revealed a large cluster of down regulated genes that encode translational proteins, especially those with ribosome biogenesis functions. As NSC319726 was first shown to have anti-cancer activity, its affects against human pathogenic fungi establish NSC319726 as a repurposed, off-patent compound that has potential antifungal activity. The minimal in vitro toxicity of lead optimized NSC319726 and its reasonable inhibitory activity against pathogens suggest advancing this compound to in vivo toxicity testing and protection studies against candidiasis.

PMID: 29209049 [PubMed - indexed for MEDLINE]

Small Molecules to Improve ER Proteostasis in Disease.

Trends Pharmacol Sci. 2019 Jul 31;:

Authors: Gonzalez-Teuber V, Albert-Gasco H, Auyeung VC, Papa FR, Mallucci GR, Hetz C

Abstract
Abnormally high levels of misfolded proteins in the endoplasmic reticulum (ER) lumen result in a stress state that contributes to the progression of several pathological conditions including diabetes, cancer, neurodegeneration, and immune dysregulation. ER stress triggers a dynamic signaling pathway known as the unfolded protein response (UPR). The UPR enforces adaptive or cell death programs by integrating information about the intensity and duration of the stress stimuli. Thus, depending on the disease context, ER stress signaling can be beneficial or detrimental. We discuss current efforts to develop small molecules to target distinct components of the UPR, and their possible applications in treating human disease, focusing on neurodegenerative diseases, metabolic disorders, and cancer.

PMID: 31377018 [PubMed - as supplied by publisher]

A genome-wide positioning systems network algorithm for in silico drug repurposing.

Nat Commun. 2019 Aug 02;10(1):3476

Authors: Cheng F, Lu W, Liu C, Fang J, Hou Y, Handy DE, Wang R, Zhao Y, Yang Y, Huang J, Hill DE, Vidal M, Eng C, Loscalzo J

Abstract
Recent advances in DNA/RNA sequencing have made it possible to identify new targets rapidly and to repurpose approved drugs for treating heterogeneous diseases by the 'precise' targeting of individualized disease modules. In this study, we develop a Genome-wide Positioning Systems network (GPSnet) algorithm for drug repurposing by specifically targeting disease modules derived from individual patient's DNA and RNA sequencing profiles mapped to the human protein-protein interactome network. We investigate whole-exome sequencing and transcriptome profiles from ~5,000 patients across 15 cancer types from The Cancer Genome Atlas. We show that GPSnet-predicted disease modules can predict drug responses and prioritize new indications for 140 approved drugs. Importantly, we experimentally validate that an approved cardiac arrhythmia and heart failure drug, ouabain, shows potential antitumor activities in lung adenocarcinoma by uniquely targeting a HIF1α/LEO1-mediated cell metabolism pathway. In summary, GPSnet offers a network-based, in silico drug repurposing framework for more efficacious therapeutic selections.

PMID: 31375661 [PubMed - in process]

Gastroprotective effect of cilostazol against ethanol- and pylorus ligation-induced gastric lesions in rats.

Naunyn Schmiedebergs Arch Pharmacol. 2019 Aug 01;:

Authors: Moawad H, El Awdan SA, Sallam NA, El-Eraky WI, Alkhawlani MA

Abstract
Despite the availability of effective antiulcer medications, their suboptimal safety profile ignites the search for alternative/complementary treatments. Drug repositioning is an attractive, efficient, and low-risk strategy. Cilostazol, a clinically used phosphodiesterase 3 inhibitor, has pronounced anti-inflammatory and vasodilatory effects suggesting antiulcer activity. Using ethanol-induced and pyloric ligation-induced gastric ulcer models, we investigated the gastroprotective effect of cilostazol (5 or 10 mg/kg, p.o.) in comparison with the standard antiulcer ranitidine (50 mg/kg, p.o.) in rats. Gastric mucosa was examined macroscopically, histologically, and biochemically for ulcer severity, markers of oxidative stress, proinflammatory cytokines, apoptotic, and cytoprotective mediators. Gastric acidic output, peptic activity, and mucin content were measured in gastric fluids. Pretreatment with cilostazol reduced ulcer number and severity, ameliorated redox status (reduced glutathione and malonaldehyde content), and decreased levels of IL-1β, IL-6, and TNF-훼 in gastric mucosa, in parallel with increases in mucosal defensive factors nitric oxide (NO), prostaglandin E2 (PGE2), and heat-shock protein 70 (HSP70) promoting mucus secretion, tissue perfusion, and regeneration. Histological examination confirmed the beneficial effects of cilostazol in terms of reducing focal necrosis and infiltration of inflammatory cells, as well as increasing mucopolysaccharide content. These beneficial effects are likely secondary to an increase in cAMP and decrease in apoptosis regulator Bcl-2-associated X protein (BAX). Cilostazol, in a dose-dependent effect, exhibited vasodilatory, anti-inflammatory, and antiapoptotic actions in the gastric mucosa resulting in significant antiulcer activity comparable with the standard drug, ranitidine, but devoid of antisecretory activity. Therefore, its use should be dose and ulcer-inducer dependent.

PMID: 31372695 [PubMed - as supplied by publisher]

Inhibitory mechanism of an anticancer drug, Bexarotene against Amyloid β peptide aggregation: Repurposing via neuroinformatics approach.

Curr Pharm Des. 2019 Aug 01;:

Authors: Bibi N, Danish Rizvi SM, Batool A, Kamal MA

Abstract
Aggregation of Amyloid β (Aβ) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, Aβ peptides are misfolded and aggregated to frame amyloid fibrils, that is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-Aβ aggregation potential. Interestingly, in the last few decades, drug repurposing has turned into a fruitful and savvy approach for the treatment of several diseases. Bexarotene is an anticancer drug that has been under consideration for its ability to suppress Aβ-peptide aggregation. However, the exact mechanistic aspect of suppression of Aβ-peptide accumulation has not yet been completely revealed. In the present study, we have attempted to decipher the mechanistic aspects of anti-aggregation potential of bexarotene by using the computational biology approach. We have observed the effect of 'Aβ-bexarotene' interaction on the aggregation ability of the Aβ-peptide and decoded the involvement of receptor for advanced glycation end products (RAGE) and beta-secretase (BACE-1). Deep structural analysis of Aβ upon binding with bexarotene revealed critical binding sites and structural twists involved in Aβ aggregation. It is evident from the present that bexarotene could significantly restrain the process of primary nucleation of Aβ. In addition, bexarotene showed a strong interaction with RAGE and BACE-1, suggesting them as plausible targets for the neuro-therapeutic action of bexarotene. Hence, we could safely suggest that bexarotene is a potent drug candidate that could reduce Aβ-peptide aggregation via applying different mechanistic pathways. These results might boost the portfolio of pharmaceutical companies looking for the development of new chemical entity against AD.

PMID: 31368868 [PubMed - as supplied by publisher]