Microbiol Spectr. 2023 May 8:e0087323. doi: 10.1128/spectrum.00873-23. Online ahead of print.

ABSTRACT

By adulthood, the majority of the population is persistently infected with BK polyomavirus (BKPyV). Only a subset of the population, generally transplant recipients on immunosuppressive drugs, will experience disease from BKPyV, but those who do have few treatment options and, frequently, poor outcomes, because to date there are no effective antivirals to treat or approved vaccines to prevent BKPyV. Most studies of BKPyV have been performed on bulk populations of cells, and the dynamics of infection at single-cell resolution have not been explored. As a result, much of our knowledge is based upon the assumption that all cells within a greater population are behaving the same way with respect to infection. The present study examines BKPyV infection on a single-cell level using high-content microscopy to measure and analyze the viral protein large T antigen (TAg), promyelocytic leukemia protein (PML), DNA, and nuclear morphological features. We observed significant heterogeneity among infected cells, within and across time points. We found that the levels of TAg within individual cells did not necessarily increase with time and that cells with the same TAg levels varied in other ways. Overall, high-content, single-cell microscopy is a novel approach to studying BKPyV that enables experimental insight into the heterogenous nature of the infection. IMPORTANCE BK polyomavirus (BKPyV) is a human pathogen that infects nearly everyone by adulthood and persists throughout a person's life. Only people with significant immune suppression develop disease from the virus, however. Until recently the only practical means of studying many viral infections was to infect a group of cells in the laboratory and measure the outcomes in that group. However, interpreting these bulk population experiments requires the assumption that infection influences all cells within a group similarly. This assumption has not held for multiple viruses tested so far. Our study establishes a novel single-cell microscopy assay for BKPyV infection. Using this assay, we discovered differences among individual infected cells that have not been apparent in bulk population studies. The knowledge gained in this study and the potential for future use demonstrate the power of this assay as a tool for understanding the biology of BKPyV.

PMID:37154756 | DOI:10.1128/spectrum.00873-23

Front Endocrinol (Lausanne). 2023 Apr 21;14:1189508. doi: 10.3389/fendo.2023.1189508. eCollection 2023.

NO ABSTRACT

PMID:37152971 | PMC:PMC10161729 | DOI:10.3389/fendo.2023.1189508

Front Endocrinol (Lausanne). 2023 Apr 21;14:1145111. doi: 10.3389/fendo.2023.1145111. eCollection 2023.

ABSTRACT

Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy.

PMID:37152929 | PMC:PMC10160627 | DOI:10.3389/fendo.2023.1145111

Int J Biol Sci. 2023 Apr 23;19(7):2270-2288. doi: 10.7150/ijbs.81415. eCollection 2023.

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most lethal malignant cancers across the world. It has a poor prognosis and lacks effective therapies, especially for patients with advanced-stage cancer, indicating an urgent need for new therapies and novel therapeutic targets. Here, by screening the U.S. Food and Drug Administration drug library against HCC cell lines, we identified that flubendazole, a traditional anthelmintic drug, could prominently suppress HCC cells in vivo and in vitro. RNA sequence analysis and cellular thermal shift assays showed that flubendazole reduced the expression of PCSK9 protein by direct targeting. The increased expression of PCSK9 in HCC tissues was demonstrated to be correlated with poor prognosis, and the inhibitory ability of flubendazole was selectively dependent on PCSK9 expression. PCSK9 knockdown abolished the antitumor effects of flubendazole in HCC. Mechanistically, flubendazole inhibited the Hedgehog signaling pathway induced by PCSK9, resulting in the downregulation of smoothened (SMO) and GLI Family Zinc Finger 1 (Gli1). Moreover, combining flubendazole with lenvatinib was found more effective than administering lenvatinib only for HCC treatment in vivo and in vitro. These findings reveal the therapeutic potential of flubendazole against HCC and provide clues on new repurposed drugs and targets for cancer treatment.

PMID:37151886 | PMC:PMC10158015 | DOI:10.7150/ijbs.81415

Sci Rep. 2023 May 5;13(1):7320. doi: 10.1038/s41598-023-33279-9.

ABSTRACT

The concept of "one target, one drug, one disease" is not always true, as compounds with previously described therapeutic applications can be useful to treat other maladies. For example, acridine derivatives have several potential therapeutic applications. In this way, identifying new potential targets for available drugs is crucial for the rational management of diseases. Computational methodologies are interesting tools in this field, as they use rational and direct methods. Thus, this study focused on identifying other rational targets for acridine derivatives by employing inverse virtual screening (IVS). This analysis revealed that chitinase enzymes can be potential targets for these compounds. Subsequently, we coupled molecular docking consensus analysis to screen the best chitinase inhibitor among acridine derivatives. We observed that 3 compounds displayed potential enhanced activity as fungal chitinase inhibitors, showing that compound 5 is the most active molecule, with an IC50 of 0.6 ng/µL. In addition, this compound demonstrated a good interaction with the active site of chitinases from Aspergillus fumigatus and Trichoderma harzianum. Additionally, molecular dynamics and free energy demonstrated complex stability for compound 5. Therefore, this study recommends IVS as a powerful tool for drug development. The potential applications are highlighted as this is the first report of spiro-acridine derivatives acting as chitinase inhibitors that can be potentially used as antifungal and antibacterial candidates.

PMID:37147323 | PMC:PMC10163251 | DOI:10.1038/s41598-023-33279-9

J Cyst Fibros. 2023 May 3:S1569-1993(23)00067-X. doi: 10.1016/j.jcf.2023.03.004. Online ahead of print.

ABSTRACT

BACKGROUND: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF.

METHODS: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators.

RESULTS: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy.

CONCLUSION: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies.

ONE-SENTENCE SUMMARY: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

PMID:37147251 | DOI:10.1016/j.jcf.2023.03.004

Cell Stem Cell. 2023 May 4;30(5):632-647.e10. doi: 10.1016/j.stem.2023.04.006.

ABSTRACT

Schwann cells (SCs) are the primary glia of the peripheral nervous system. SCs are involved in many debilitating disorders, including diabetic peripheral neuropathy (DPN). Here, we present a strategy for deriving SCs from human pluripotent stem cells (hPSCs) that enables comprehensive studies of SC development, physiology, and disease. hPSC-derived SCs recapitulate the molecular features of primary SCs and are capable of in vitro and in vivo myelination. We established a model of DPN that revealed the selective vulnerability of SCs to high glucose. We performed a high-throughput screen and found that an antidepressant drug, bupropion, counteracts glucotoxicity in SCs. Treatment of hyperglycemic mice with bupropion prevents their sensory dysfunction, SC death, and myelin damage. Further, our retrospective analysis of health records revealed that bupropion treatment is associated with a lower incidence of neuropathy among diabetic patients. These results highlight the power of this approach for identifying therapeutic candidates for DPN.

PMID:37146583 | DOI:10.1016/j.stem.2023.04.006

PLoS Comput Biol. 2023 May 5;19(5):e1011050. doi: 10.1371/journal.pcbi.1011050. Online ahead of print.

ABSTRACT

Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.

PMID:37146076 | DOI:10.1371/journal.pcbi.1011050

Adv Sci (Weinh). 2023 May 5:e2301661. doi: 10.1002/advs.202301661. Online ahead of print.

ABSTRACT

Intratumoral CD8+ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self-degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME-responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2-like tumor-associated macrophages, and 3) downregulating PD-L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8+ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti-PD-1 antibodies.

PMID:37144520 | DOI:10.1002/advs.202301661

Cancer Sci. 2023 May 4. doi: 10.1111/cas.15827. Online ahead of print.

ABSTRACT

Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.

PMID:37142416 | DOI:10.1111/cas.15827

Cell Death Differ. 2023 May 4. doi: 10.1038/s41418-023-01167-4. Online ahead of print.

ABSTRACT

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.

PMID:37142656 | DOI:10.1038/s41418-023-01167-4

Bioorg Med Chem. 2023 Apr 25;86:117294. doi: 10.1016/j.bmc.2023.117294. Online ahead of print.

ABSTRACT

Drug repurposing is a distinguished approach for drug development that saves a great deal of time and money. Based on our previous successful repurposing of a compound BMMP from anti-HIV-1 therapy to anti-cancer metastatic activity, we adopted the same techniques for repurposing benzimidazole derivatives considering MM-1 as a lead compound. An extensive structure-activity relationship (SAR) study afforded three promising compounds, MM-1d, MM-1h, and MM-1j, which inhibited cell migration in a similar fashion to BMMP. These compounds suppressed CD44 mRNA expression, whereas only MM-1h further suppressed mRNA expression of the epithelial-mesenchymal transition (EMT) marker zeb 1. Using benzimidazole instead of methyl pyrimidine as in BMMP resulted in better affinity for heterogeneous nuclear ribonucleoprotein (hnRNP) M protein and higher anti-cell migration activity. In conclusion, our study identified new agents that surpass the affinity of BMMP for hnRNP M and have anti-EMT activity, which makes them worthy of future attention and optimization.

PMID:37141680 | DOI:10.1016/j.bmc.2023.117294

Acta Pharm Sin B. 2023 Apr;13(4):1671-1685. doi: 10.1016/j.apsb.2022.08.023. Epub 2022 Sep 5.

ABSTRACT

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

PMID:37139418 | PMC:PMC10149898 | DOI:10.1016/j.apsb.2022.08.023

PeerJ Comput Sci. 2017 Feb 13;3:e106. doi: 10.7717/peerj-cs.106. eCollection 2017.

ABSTRACT

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates; however, filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an application programming interface or web interface, and has generated 25 high-quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

PMID:37133296 | PMC:PMC10151034 | DOI:10.7717/peerj-cs.106

ArXiv. 2023 Apr 18:arXiv:2304.09344v1. Preprint.

ABSTRACT

Knowledge graphs are an increasingly common data structure for representing biomedical information. These knowledge graphs can easily represent heterogeneous types of information, and many algorithms and tools exist for querying and analyzing graphs. Biomedical knowledge graphs have been used in a variety of applications, including drug repurposing, identification of drug targets, prediction of drug side effects, and clinical decision support. Typically, knowledge graphs are constructed by centralization and integration of data from multiple disparate sources. Here, we describe BioThings Explorer, an application that can query a virtual, federated knowledge graph derived from the aggregated information in a network of biomedical web services. BioThings Explorer leverages semantically precise annotations of the inputs and outputs for each resource, and automates the chaining of web service calls to execute multi-step graph queries. Because there is no large, centralized knowledge graph to maintain, BioThing Explorer is distributed as a lightweight application that dynamically retrieves information at query time. More information can be found at https://explorer.biothings.io, and code is available at https://github.com/biothings/biothings_explorer.

PMID:37131885 | PMC:PMC10153288

bioRxiv. 2023 Apr 19:2023.04.19.537517. doi: 10.1101/2023.04.19.537517. Preprint.

ABSTRACT

Fungal pathogens like Candida albicans can cause devastating human disease. Treatment of candidemia is complicated by the high rate of resistance to common antifungal therapies. Additionally, there is host toxicity associated with many antifungal compounds due to the conservation between essential mammalian and fungal proteins. An attractive new approach for antimicrobial development is to target virulence factors: non-essential processes that are required for the organism to cause disease in human hosts. This approach expands the potential target space while reducing the selective pressure towards resistance, as these targets are not essential for viability. In C. albicans, a key virulence factor is the ability to transition to hyphal morphology. We developed a high-throughput image analysis pipeline to distinguish between yeast and filamentous growth in C. albicans at the single cell level. Based on this phenotypic assay, we screened the FDA drug repurposing library of 2,017 compounds for their ability to inhibit filamentation and identified 33 compounds that block the hyphal transition in C. albicans with IC 50 values ranging from 0.2 to 150 µM. Multiple compounds showed a phenyl vinyl sulfone chemotype, prompting further analysis. Of these phenyl vinyl sulfones, NSC 697923 displayed the most efficacy, and by selecting for resistant mutants, we identified eIF3 as the target of NSC 697923 in C. albicans .

PMID:37131825 | PMC:PMC10153179 | DOI:10.1101/2023.04.19.537517

bioRxiv. 2023 Apr 19:2023.04.19.537449. doi: 10.1101/2023.04.19.537449. Preprint.

ABSTRACT

Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may therefore display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP dependent cellular growth.

PMID:37131806 | PMC:PMC10153145 | DOI:10.1101/2023.04.19.537449

Res Sq. 2023 Apr 18:rs.3.rs-2809689. doi: 10.21203/rs.3.rs-2809689/v1. Preprint.

ABSTRACT

Background Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor; however, treatment remains a significant challenge. This study aims to identify drug repurposing candidates for GBM by developing an integrative rare disease profile network containing heterogeneous types of biomedical data. Methods We developed a Glioblastoma-based Biomedical Profile Network (GBPN) by extracting and integrating biomedical information pertinent to GBM-related diseases from the NCATS GARD Knowledge Graph (NGKG). We further clustered the GBPN based on modularity classes which resulted in multiple focused subgraphs, named mc_GBPN. We then identified high-influence nodes by performing network analysis over the mc_GBPN and validated those nodes that could be potential drug repositioning candidates for GBM. Results We developed the GBPN with 1,466 nodes and 107,423 edges and consequently the mc_GBPN with forty-one modularity classes. A list of the ten most influential nodes were identified from the mc_GBPN. These notably include Riluzole, stem cell therapy, cannabidiol, and VK-0214, with proven evidence for treating GBM. Conclusion Our GBM-targeted network analysis allowed us to effectively identify potential candidates for drug repurposing. This could lead to less invasive treatments for glioblastoma while significantly reducing research costs by shortening the drug development timeline. Furthermore, this workflow can be extended to other disease areas.

PMID:37131675 | PMC:PMC10153381 | DOI:10.21203/rs.3.rs-2809689/v1

AMIA Annu Symp Proc. 2023 Apr 29;2022:1163-1172. eCollection 2022.

ABSTRACT

Adverse event reports (AER) are widely used for post-market drug safety surveillance and drug repurposing, with the assumption that drugs with similar side-effects may have similar therapeutic effects also. In this study, we used distributed representations of drugs derived from the Food and Drug Administration (FDA) AER system using aer2vec, a method of representing AER, with drug embeddings emerging from a neural network trained to predict the probability of adverse drug effects given observed drugs. We combined these representations with molecular features to predict permeability of the blood-brain barrier to drugs, a prerequisite to their application to treat conditions of the central nervous system. Across multiple machine learning classifiers, the addition of distributed representations improved performance over prior methods using drug-drug similarity estimates derived from discrete representations of AER system data. Embedding-based approaches outperformed those using discrete statistics, with improvements in absolute AUC of 5% and 9%, corresponding to improvements of 9% and 13% over performance with molecular features only. Performance was retained when reducing embedding dimensions from 500 to 6, indicating that they are neither attributable to overfitting, nor to a difference in the number of trainable parameters. These results indicate that aer2vec distributed representations carry information that is valuable for drug repurposing.

PMID:37128462 | PMC:PMC10148361

Curr Drug Res Rev. 2023 Apr 29. doi: 10.2174/2589977515666230430004013. Online ahead of print.

ABSTRACT

BACKGROUND: Mucormycosis has been infesting the universe for a while back, often with no prompt treatments. The disease devastation is spreading at an alarming rate. Many researchers are still hoping for a good potential drug that could help the healthcare system in this tussle. Molecular docking is an in silico tool that has gained popularity over the last few decades. Knowing the mechanism of enzymatic action is aided by imitating membrane protein actions in binding ligands.

AIM: The aim of this perspective is to determine whether an existing drug, daclatasvir, has antifungal activity.

OBJECTIVE: The primary objective of this in silico study was to investigate the potential effects of the binding affinity of daclatasvir with the crucial protein (1XFF) of mucormycosis, as well as the binding pattern of the active site amino acids with the drug molecule.

MATERIALS AND METHODS: To calculate the binding affinity of daclatasvir to the fungal protein 1XFF, Auto Dock Vina was used for molecular docking studies. The CDOCKER protocol was used to determine the receptor-ligand interaction by configuring various parameters.

RESULTS: The docking energy of the ligand (daclatasvir) on the protein (1XFF) was found to be -16.7216 kcal/mol, while the interaction energy was found to be - 42.1314 kcal/mol.

CONCLUSION: The binding pattern completely alters the dynamics of the protein, resulting in the breakdown of the fungal wall. The vital protein (1XFF) of Rhizopus oryzae is proposed as a possible protein target for the non-structural protein 5A inhibitor/antiviral drug daclatasvir in this study.

PMID:37125653 | DOI:10.2174/2589977515666230430004013