Cell Rep Med. 2021 May 18;2(5):100281. doi: 10.1016/j.xcrm.2021.100281. eCollection 2021 May 18.

ABSTRACT

Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

PMID:34095883 | PMC:PMC8149471 | DOI:10.1016/j.xcrm.2021.100281

ACS Omega. 2021 May 19;6(21):13870-13887. doi: 10.1021/acsomega.1c01526. eCollection 2021 Jun 1.

ABSTRACT

AIM/HYPOTHESIS: The complexity and heterogeneity of multiple pathological features make Alzheimer's disease (AD) a major culprit to global health. Drug repurposing is an inexpensive and reliable approach to redirect the existing drugs for new indications. The current study aims to study the possibility of repurposing approved anticancer drugs for AD treatment. We proposed an in silico pipeline based on "omics" data mining that combines genomics, transcriptomics, and metabolomics studies. We aimed to validate the neuroprotective properties of repurposed drugs and to identify the possible mechanism of action of the proposed drugs in AD.

RESULTS: We generated a list of AD-related genes and then searched DrugBank database and Therapeutic Target Database to find anticancer drugs related to potential AD targets. Specifically, we researched the available approved anticancer drugs and excluded the information of investigational and experimental drugs. We developed a computational pipeline to prioritize the anticancer drugs having a close association with AD targets. From data mining, we generated a list of 2914 AD-related genes and obtained 49 potential druggable targets by functional enrichment analysis. The protein-protein interaction (PPI) studies for these genes revealed 641 interactions. We found that 15 AD risk/direct PPI genes were associated with 30 approved oncology drugs. The computational validation of candidate drug-target interactions, structural and functional analysis, investigation of related molecular mechanisms, and literature-based analysis resulted in four repurposing candidates, of which three drugs were epidermal growth factor receptor (EGFR) inhibitors.

CONCLUSION: Our computational drug repurposing approach proposed EGFR inhibitors as potential repurposing drugs for AD. Consequently, our proposed framework could be used for drug repurposing for different indications in an economical and efficient way.

PMID:34095679 | PMC:PMC8173619 | DOI:10.1021/acsomega.1c01526

Alzheimers Dement (N Y). 2021 May 27;7(1):e12182. doi: 10.1002/trc2.12182. eCollection 2021.

ABSTRACT

INTRODUCTION: Cilostazol may be a novel therapeutic agent for Alzheimer's disease. Its metabolite, OPC-13015, has a stronger inhibitory effect on type 3 phosphodiesterase than cilostazol.

METHODS: We prospectively enrolled patients with mild cognitive impairment to whom cilostazol was newly prescribed. Patients underwent the Montreal Cognitive Assessment (MoCA) twice, at a 6-month interval. Plasma cilostazol, OPC-13015, OPC-13213, and OPC-13217 concentrations were determined using liquid chromatography-tandem mass spectrometry.

RESULTS: MoCA score changes from baseline to the 6-month visit were positively correlated with ratios of OPC-13015 to cilostazol and total metabolites (n = 19, P = .005). Patients with higher ratios of OPC-13015 (≥0.18, median value; n = 10) had significantly higher MoCA scores (P = .036) than patients with lower ratios (the ratio <0.18, n = 9). The absolute value of OPC-13015 concentration in blood was also higher in patients with preserved cognitive function (P = .033).

DISCUSSION: Blood OPC-13015 levels may be a predictive biomarker of cilostazol treatment for Alzheimer's disease.

PMID:34095441 | PMC:PMC8158162 | DOI:10.1002/trc2.12182

Futur J Pharm Sci. 2021;7(1):113. doi: 10.1186/s43094-021-00259-7. Epub 2021 Jun 2.

ABSTRACT

BACKGROUND: Following the outbreak of the COVID-19 pandemic, there was a surge of research activity to find methods/drugs to treat it. There has been drug-repurposing research focusing on traditional medicines. Concomitantly, many researchers tried to find in silico evidence for traditional medicines. There is a great increase in article publication to commensurate the new-found research interests. This situation inspired the authors to have a comprehensive understanding of the multitude of publications related to the COVID-19 pandemic with a wish to get promising drug leads.

MAIN BODY: This review article has been conceived and made as a hybrid of the review of the selected papers advertised recently and produced in the interest of the COVID-19 situation, and in silico work done by the authors. The outcome of the present review underscores a recommendation for thorough MDS analyses of the promising drug leads. The inclusion of in silico work as an addition to the review was motivated by a recently published article of Toelzer and colleagues. The in silico investigation of free fatty acids is novel to the field and it buttresses the further MDS analysis of drug leads for managing the COVID-19 pandemic.

CONCLUSION: The review performed threw light on the need for MDS analyses to be considered together with the application of other in silico methods of prediction of pharmacologic properties directing towards the sites of drug-receptor regulation. Also, the present analysis would help formulate new recipes for complementary medicines.

PMID:34095323 | PMC:PMC8170460 | DOI:10.1186/s43094-021-00259-7

Front Oncol. 2021 May 20;11:660943. doi: 10.3389/fonc.2021.660943. eCollection 2021.

ABSTRACT

Cancer is a complex group of diseases that constitute the second largest cause of mortality worldwide. The development of new drugs for treating this disease is a long and costly process, from the discovery of the molecule through testing in phase III clinical trials, a process during which most candidate molecules fail. The use of drugs currently employed for the management of other diseases (drug repurposing) represents an alternative for developing new medical treatments. Repurposing existing drugs is, in principle, cheaper and faster than developing new drugs. Antihypertensive drugs, primarily belonging to the pharmacological categories of angiotensin-converting enzyme inhibitors, angiotensin II receptors, direct aldosterone antagonists, β-blockers and calcium channel blockers, are commonly prescribed and have well-known safety profiles. Additionally, some of these drugs have exhibited pharmacological properties useful for the treatment of cancer, rendering them candidates for drug repurposing. In this review, we examine the preclinical and clinical evidence for utilizing antihypertensive agents in the treatment of cancer.

PMID:34094953 | PMC:PMC8173186 | DOI:10.3389/fonc.2021.660943

Bioorg Chem. 2021 May 31;113:105035. doi: 10.1016/j.bioorg.2021.105035. Online ahead of print.

ABSTRACT

We managed to repurpose the old drug iodoquinol to a series of novel anticancer 7-iodo-quinoline-5,8-diones. Twelve compounds were identified as inhibitors of moderate to high potency on an inhouse MCF-7 cell line, of which 2 compounds (5 and 6) were capable of reducing NAD level in MCF-7 cells in concentrations equivalent to half of their IC50s, potentially due to NAD(P)H quinone oxidoreductase (NQO1) inhibition. The same 2 compounds (5 and 6) were capable of reducing p53 expression and increasing reactive oxygen species levels, which further supports the NQO-1 inhibitory activity. Furthermore, 4 compounds (compounds 5-7 and 10) were qualified by the Development Therapeutic Program (DTP) division of the National Cancer Institute (NCI) for full panel five-dose in vitro assay to determine their GI50 on the 60 cell lines. All five compounds showed broad spectrum sub-micromolar to single digit micromolar GI50 against a wide range of cell lines. Cell cycle analysis and dual staining assays with annexin V-FITC/propidium iodide on MCF-7 cells confirmed the capability of the most active compound (compound 5) to induce cell cycle arrest at Pre-G1 and G2/M phases as well as apoptosis. Both cell cycle arrest and apoptosis were affirmed at the molecular level by the ability of compound 5 to enhance the expression levels of caspase-3 and Bax together with suppressing that of CDK1 and Bcl-2. Additionally, an anti-angiogenic effect was evident with compound 5 as supported by the decreased expression of VEGF. Interesting binding modes within NQO-1 active site had been identified and confirmed by both molecular docking and dymanic experiments.

PMID:34091287 | DOI:10.1016/j.bioorg.2021.105035

Mayo Clin Proc. 2021 Jun;96(6):1592-1608. doi: 10.1016/j.mayocp.2021.04.008. Epub 2021 Apr 21.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic continues its global spread. Coordinated effort on a vast scale is required to halt its progression and to save lives. Electronic health record (EHR) data are a valuable resource to mitigate the COVID-19 pandemic. We review how the EHR could be used for disease surveillance and contact tracing. When linked to "omics" data, the EHR could facilitate identification of genetic susceptibility variants, leading to insights into risk factors, disease complications, and drug repurposing. Real-time monitoring of patients could enable early detection of potential complications, informing appropriate interventions and therapy. We reviewed relevant articles from PubMed, MEDLINE, and Google Scholar searches as well as preprint servers, given the rapidly evolving understanding of the COVID-19 pandemic.

PMID:34088418 | DOI:10.1016/j.mayocp.2021.04.008

J Gynecol Oncol. 2021 Jul;32(4):e65. doi: 10.3802/jgo.2021.32.e65.

ABSTRACT

OBJECTIVE: Investigation of new drugs (INDs) is a tremendously inefficient process in terms of time and cost. Drug repositioning is another method used to investigate potential new agents in well-known drugs. This study assessed the survival impact of metformin medication on ovarian cancer.

METHODS: A national sample cohort of the Korean National Health Insurance Service Data was analyzed. Cox proportional hazards regression was used to analyzing hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for underlying diseases and medications as confounding factors for overall survival (OS) and cancer-specific survival (CSS).

RESULTS: A total of 866 eligible patients were included from among 1,025,340 cohort participants. Among them, 101 (11.7%) were metformin users. No difference in OS was observed between non-users and users. No difference in OS was observed according to age and Charlson Comorbidity Index. Long-term metformin use (≥720 days) was associated with better OS (adjusted HR=0.244; 95% CI=0.090-0.664; p=0.006). A multivariate Cox proportional hazards model showed that long-term metformin use was an independent favorable prognostic factor for OS (HR=0.193; 95% CI=0.070-0.528; p=0.001) but not for CSS (HR=0.599; 95% CI=0.178-2.017; p=0.408).

CONCLUSION: Long-term metformin use reduced all-cause mortality, but not CSS in ovarian cancer. Whether metformin itself reduces deaths because of ovarian cancer requires further investigation.

PMID:34085799 | DOI:10.3802/jgo.2021.32.e65

Nat Commun. 2021 Jun 3;12(1):3309. doi: 10.1038/s41467-021-23328-0.

ABSTRACT

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

PMID:34083527 | DOI:10.1038/s41467-021-23328-0

Expert Opin Ther Pat. 2021 Jun 3. doi: 10.1080/13543776.2021.1939308. Online ahead of print.

ABSTRACT

INTRODUCTION: Mucormycosis is an uncommon but life-threatening infection with non-specific clinical manifestations that make its diagnosis/treatment difficult. The current literature indicates that mucormycosis case incidences are on the rise in developing and developed countries, and, unfortunately, there are only a few treatments available. Accordingly, it is essential to provide more treatment options for mucormycosis.

AREA COVERED: This patent review focuses on the granted patents and patent applications related to medication for mucormycosis treatment from the publication year of the amphotericin-B patent application (1958) till January 30, 2021.

EXPERT OPINION: Mucormycosis has few available treatments, including amphotericin-B, isavuconazonium sulfate, posaconazole, or their combination. A few anti-mucormycosis medicines are under clinical development. The exact burden of mucormycosis is unknown, but it is expected to be more than the reported cases because of mucormycosis epidemiological changes. This patent review has shown that scientists are progressing towards developing a new treatment for mucormycosis in the form of new chemical compounds, new drug combinations and dosage forms, vaccines, plant products, drug repurposing, and derivatives of the biomolecules. This progress is encouraging to fight this devastating illness.

PMID:34082658 | DOI:10.1080/13543776.2021.1939308

Brief Bioinform. 2021 Jun 3:bbab211. doi: 10.1093/bib/bbab211. Online ahead of print.

ABSTRACT

The COVID-19 pandemic calls for rapid development of effective treatments. Although various drug repurpose approaches have been used to screen the FDA-approved drugs and drug candidates in clinical phases against SARS-CoV-2, the coronavirus that causes this disease, no magic bullets have been found until now. In this study, we used directed message passing neural network to first build a broad-spectrum anti-beta-coronavirus compound prediction model, which gave satisfactory predictions on newly reported active compounds against SARS-CoV-2. Then, we applied transfer learning to fine-tune the model with the recently reported anti-SARS-CoV-2 compounds and derived a SARS-CoV-2 specific prediction model COVIDVS-3. We used COVIDVS-3 to screen a large compound library with 4.9 million drug-like molecules from ZINC15 database and recommended a list of potential anti-SARS-CoV-2 compounds for further experimental testing. As a proof-of-concept, we experimentally tested seven high-scored compounds that also demonstrated good binding strength in docking studies against the 3C-like protease of SARS-CoV-2 and found one novel compound that can inhibit the enzyme. Our model is highly efficient and can be used to screen large compound databases with millions or more compounds to accelerate the drug discovery process for the treatment of COVID-19.

PMID:34081143 | DOI:10.1093/bib/bbab211

J Biomol Struct Dyn. 2021 Jun 3:1-15. doi: 10.1080/07391102.2021.1930583. Online ahead of print.

ABSTRACT

Alzheimer disease (AD) is the most common, irreversible and progressive form of dementia for which the exact pathology and cause are still not clear. At present, we are only confined to symptomatic treatment, and the lack of disease-modifying therapeutics is worrisome. Alteration of Wnt signaling has been linked to metabolic diseases as well as AD. The crosstalk between Canonical Wnt signaling and insulin signaling pathway has been widely studied and accepted from several clinical and preclinical studies that have proven the beneficial effect of antidiabetic medications in the case of memory and cognition loss. This structure-based in silico study was focused on exploring the link between the currently available FDA approved antidiabetic drugs and the Wnt signaling pathway. The library of antidiabetics was obtained from drug bank and was screened for their binding affinity with protein (PDB ID: 3S2K) LRP6, a coreceptor of the Wnt signaling pathway using GLIDE module of Schrodinger. The top molecules, with higher docking score, binding energy and stable interactions, were subjected to energy-based calculation using MMGBSA, followed by a molecular dynamics-based simulation study. Drugs of class α-glucosidase inhibitors and peroxisome proliferator-activated receptors (PPARs) agonists were found to have a strong affinity towards LRP6 proteins, highlighting the possibility of the modulation of Wnt signaling by antidiabetics as one of the possible mechanisms for use in AD. However, further experimental based in vitro and in vivo studies are warranted for verification and support.Communicated by Ramaswamy H. Sarma.

PMID:34080526 | DOI:10.1080/07391102.2021.1930583

Front Cell Infect Microbiol. 2021 May 17;11:684515. doi: 10.3389/fcimb.2021.684515. eCollection 2021.

ABSTRACT

Drug repurposing, or identifying new uses for existing drugs, has emerged as an alternative to traditional drug discovery processes involving de novo synthesis. Drugs that are currently approved or under development for non-antibiotic indications may possess antibiotic properties, and therefore may have repurposing potential, either alone or in combination with an antibiotic. They might also serve as "antibiotic adjuvants" to enhance the activity of certain antibiotics.

PMID:34079770 | PMC:PMC8165386 | DOI:10.3389/fcimb.2021.684515

Br J Nutr. 2021 Jun 3:1-6. doi: 10.1017/S0007114521001847. Online ahead of print.

NO ABSTRACT

PMID:34078498 | DOI:10.1017/S0007114521001847

Cell Rep. 2021 Jun 1;35(9):109202. doi: 10.1016/j.celrep.2021.109202.

ABSTRACT

Metabolic plasticity in cancer cells makes use of metabolism-targeting agents very challenging. Drug-induced metabolic rewiring may, however, uncover vulnerabilities that can be exploited. We report that resistance to glycolysis inhibitor 3-bromopyruvate (3-BrPA) arises from DNA methylation in treated cancer cells and subsequent silencing of the monocarboxylate transporter MCT1. We observe that, unexpectedly, 3-BrPA-resistant cancer cells mostly rely on glycolysis to sustain their growth, with MCT4 as an essential player to support lactate flux. This shift makes cancer cells particularly suited to adapt to hypoxic conditions and resist OXPHOS inhibitors and anti-proliferative chemotherapy. In contrast, blockade of MCT4 activity in 3-BrPA-exposed cancer cells with diclofenac or genetic knockout, inhibits growth of derived spheroids and tumors in mice. This study supports a potential mode of collateral lethality according to which metabolic adaptation of tumor cells to a first-line therapy makes them more responsive to a second-line treatment.

PMID:34077729 | DOI:10.1016/j.celrep.2021.109202

Expert Opin Drug Discov. 2021 Jun 2:1-17. doi: 10.1080/17460441.2021.1918096. Online ahead of print.

ABSTRACT

Introduction: Precision medicine is the concept of treating diseases based on environmental factors, lifestyles, and molecular profiles of patients. This approach has been found to increase success rates of clinical trials and accelerate drug approvals. However, current precision medicine applications in early drug discovery use only a handful of molecular biomarkers to make decisions, whilst clinics gear up to capture the full molecular landscape of patients in the near future. This deep multi-omics characterization demands new analysis strategies to identify appropriate treatment regimens, which we envision will be pioneered by artificial intelligence.Areas covered: In this review, the authors discuss the current state of drug discovery in precision medicine and present our vision of how artificial intelligence will impact biomarker discovery and drug design.Expert opinion: Precision medicine is expected to revolutionize modern medicine; however, its traditional form is focusing on a few biomarkers, thus not equipped to leverage the full power of molecular landscapes. For learning how the development of drugs can be tailored to the heterogeneity of patients across their molecular profiles, artificial intelligence algorithms are the next frontier in precision medicine and will enable a fully personalized approach in drug design, and thus ultimately impacting clinical practice.

PMID:34075855 | DOI:10.1080/17460441.2021.1918096

BMC Bioinformatics. 2021 Jun 1;22(Suppl 3):293. doi: 10.1186/s12859-020-03882-y.

ABSTRACT

BACKGROUND: Drug repositioning, meanings finding new uses for existing drugs, which can accelerate the processing of new drugs research and development. Various computational methods have been presented to predict novel drug-disease associations for drug repositioning based on similarity measures among drugs and diseases. However, there are some known associations between drugs and diseases that previous studies not utilized.

METHODS: In this work, we develop a deep gated recurrent units model to predict potential drug-disease interactions using comprehensive similarity measures and Gaussian interaction profile kernel. More specifically, the similarity measure is used to exploit discriminative feature for drugs based on their chemical fingerprints. Meanwhile, the Gaussian interactions profile kernel is employed to obtain efficient feature of diseases based on known disease-disease associations. Then, a deep gated recurrent units model is developed to predict potential drug-disease interactions.

RESULTS: The performance of the proposed model is evaluated on two benchmark datasets under tenfold cross-validation. And to further verify the predictive ability, case studies for predicting new potential indications of drugs were carried out.

CONCLUSION: The experimental results proved the proposed model is a useful tool for predicting new indications for drugs or new treatments for diseases, and can accelerate drug repositioning and related drug research and discovery.

PMID:34074242 | DOI:10.1186/s12859-020-03882-y

Nutrients. 2021 May 24;13(6):1784. doi: 10.3390/nu13061784.

ABSTRACT

Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb-drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.

PMID:34073784 | DOI:10.3390/nu13061784

J Clin Med. 2021 May 24;10(11):2262. doi: 10.3390/jcm10112262.

ABSTRACT

Despite improvements in understanding the pathogenic mechanisms of primary glomerular diseases, therapy still remains nonspecific. We sought to identify novel therapies targeting kidney-intrinsic injury of distinct primary glomerulonephritides through computational systems biology approaches. We defined the unique transcriptional landscape within kidneys from patients with focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN) and thin basement membrane nephropathy (TBMN). Differentially expressed genes were functionally annotated with enrichment analysis, and distinct biological processes and pathways implicated in each primary glomerular disease were uncovered. Finally, we identified novel drugs and small-molecule compounds that may reverse each glomerulonephritis phenotype, suggesting they should be further tested as precise therapy in primary glomerular diseases.

PMID:34073694 | DOI:10.3390/jcm10112262

Int J Mol Sci. 2021 May 31;22(11):5943. doi: 10.3390/ijms22115943.

ABSTRACT

Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, these infections can lead to more serious complications. The treatment of choice, metronidazole, is in doubt due to adverse effects and resistance. Therefore, there is a need for new compounds against these parasites. In this work, a structure-based virtual screening of FDA-approved drugs was performed to identify compounds with antiprotozoal activity. The glycolytic enzyme triosephosphate isomerase, present in both E. histolytica and G. lamblia, was used as the drug target. The compounds with the best average docking score on both structures were selected for the in vitro evaluation. Three compounds, chlorhexidine, tolcapone, and imatinib, were capable of inhibit growth on G. lamblia trophozoites (0.05-4.935 μg/mL), while folic acid showed activity against E. histolytica (0.186 μg/mL) and G. lamblia (5.342 μg/mL).

PMID:34073021 | DOI:10.3390/ijms22115943