Biomed Pharmacother. 2024 Oct 9;180:117542. doi: 10.1016/j.biopha.2024.117542. Online ahead of print.

ABSTRACT

A significant hurdle in cancer treatment arises from multidrug resistance (MDR), often due to overexpression of ATP-binding cassette (ABC) transporters like ABCB1 and/or ABCG2 in cancer cells. These transporters actively diminish the efficacy of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux and reducing intracellular drug accumulation in cancer cells. Addressing multidrug-resistant cancers poses a significant challenge due to the lack of approved treatments, prompting the exploration of alternative avenues like drug repurposing (also referred to as drug repositioning) of molecularly targeted agents to reverse MDR-mediated by ABCB1 and/or ABCG2 in multidrug-resistant cancer cells. Epertinib, a potent inhibitor of EGFR and HER2 currently in clinical trials for solid tumors, was investigated for its potential to resensitize ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our findings reveal that at sub-toxic, submicromolar concentrations, epertinib restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. The results demonstrate that epertinib enhances drug-induced apoptosis in these cancer cells by impeding the drug-efflux function of ABCB1 and ABCG2 without altering their expression. ATPase activity and molecular docking were employed to reveal potential interaction sites between epertinib and the drug-binding pockets of ABCB1 and ABCG2. In summary, our study demonstrates an additional pharmacological capability of epertinib against the activity of ABCB1 and ABCG2. These findings suggest that incorporating epertinib into combination therapy could be advantageous for a specific patient subset with tumors exhibiting high levels of ABCB1 or ABCG2, warranting further exploration.

PMID:39388999 | DOI:10.1016/j.biopha.2024.117542

Cell Rep. 2024 Oct 9;43(10):114818. doi: 10.1016/j.celrep.2024.114818. Online ahead of print.

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) have shown promise in cancer therapy, particularly for hepatocellular carcinoma (HCC), but their molecular targets and mechanisms remain unclear. Here, we show that SSRIs exhibit significant anti-HCC effects independent of their classical target, the serotonin reuptake transporter (SERT). Using global inverse gene expression profiling, drug affinity responsive target stability assays, and in silico molecular docking, we demonstrate that citalopram targets glucose transporter 1 (GLUT1), resulting in reduced glycolytic flux. A mutant GLUT1 variant at the citalopram binding site (E380) diminishes the drug's inhibitory effects on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth of GLUT1high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis reveals that SSRI use correlates with a lower risk of metastasis among patients with HCC. Our study describes a role for SSRIs in cancer metabolism, establishing a rationale for their repurposing as potential anti-cancer drugs for HCC.

PMID:39388353 | DOI:10.1016/j.celrep.2024.114818

RSC Med Chem. 2024 Sep 19. doi: 10.1039/d4md00449c. Online ahead of print.

ABSTRACT

Globally, the emergence of anti-microbial resistance in pathogens has become a serious threat to human health and well-being. Infections caused by drug-resistant microorganisms in hospitals are associated with increased morbidity, mortality, and healthcare costs. Acinetobacter baumannii is a Gram-negative bacterium belonging to the ESKAPE group and is widely associated with nosocomial infections. It persists in hospitals and survives antibiotic treatment, prompting acute infections such as urinary tract infections, pneumonia, bacteremia, meningitis, and wound-related infections. An innovation void in drug discovery and the lack of new therapeutic measures against A. baumannii continue to afflict infection control against the rising drug-resistant cases. The emergence of drug-resistant A. baumannii strains has also led to the incessant collapse of newly discovered antibiotics. Therefore exploring novel strategies is requisite to give impetus to A. baumannii drug discovery. The present review discusses the bacterial research community's efforts in the field of A. baumannii, focusing on the strategies adapted to identify potent scaffolds and novel targets to bolster and diversify the chemical space available for drug discovery. Firstly, we have discussed existing chemotherapy and various anti-microbial resistance mechanisms in A. baumannii bacterial strains. Next, we elaborate on multidisciplinary approaches and strategies that may be the way forward to combat the current menace caused by the drug-resistant A. baumannii strains. The review highlights the recent advances in drug discovery, including combinational therapy, high-throughput screening, drug repurposing, nanotechnology, and anti-microbial peptides, which are imperative tools to fight bacterial pathogens in the future.

PMID:39386059 | PMC:PMC11457259 | DOI:10.1039/d4md00449c

Front Pharmacol. 2024 Sep 25;15:1468920. doi: 10.3389/fphar.2024.1468920. eCollection 2024.

ABSTRACT

Glioblastoma (GBM) is the most commonly occurring and most aggressive primary brain tumor. Transcriptomics-based tumor subtype classification has established the mesenchymal lineage of GBM (MES-GBM) as cancers with particular aggressive behavior and high levels of therapy resistance. Previously it was show that Trihexyphenidyl (THP), a market approved M1 muscarinic receptor-targeting oral drug can suppress proliferation and survival of GBM stem cells from the classical transcriptomic subtype. In a series of in vitro experiments, this study confirms the therapeutic potential of THP, by effectively suppressing the growth, proliferation and survival of MES-GBM cells with limited effects on non-tumor cells. Transcriptomic profiling of treated cancer cells identified genes and associated metabolic signaling pathways as possible underlying molecular mechanisms responsible for THP-induced effects. In vivo trials of THP in immunocompromised mice carry orthotopic MES-GBMs showed moderate response to the drug. This study further highlights the potential of THP repurposing as an anti-cancer treatment regimen but mode of action and d optimal treatment procedures for in vivo regimens need to be investigated further.

PMID:39386028 | PMC:PMC11461351 | DOI:10.3389/fphar.2024.1468920

Sci Rep. 2024 Oct 10;14(1):23653. doi: 10.1038/s41598-024-71770-z.

ABSTRACT

The accumulation of monocyte-derived macrophages in the lung tissue during inflammation is important for the pathogenesis of fibrotic lung disease. Deficiencies in chemokine receptors CCR2 and CCR5 and their ligands, which mediate monocyte/macrophage migration, ameliorate bleomycin (BLM)-induced lung fibrosis. Disulfiram (DSF), which is used to treat alcoholism because of its aldehyde dehydrogenase (ALDH)-inhibiting effect, inhibits monocyte/macrophage migration by inhibiting FROUNT, an intracellular regulator of CCR2/CCR5 signalling. Here, we investigated the antifibrotic effect of oral DSF administration in a mouse model of BLM-induced lung fibrosis, focusing on macrophage response and fibrosis progression. The direct inhibitory activity of DSF on monocyte migration was measured using the Boyden chamber assay and compared with that of DSF-related inhibitors with different FROUNT-inhibition activities. Quantitative PCR was used to determine the expression of fibrosis-promoting genes in the lung tissue. DSF significantly suppressed macrophage infiltration into lung tissues and attenuated BLM-induced lung fibrosis. DSF and its metabolites, diethyldithiocarbamate (DDC) and copper diethyldithiocarbamate (Cu(DDC)2), inhibited monocyte migration toward the culture supernatant of primary mouse lung cells mainly comprising CCL2, whereas cyanamide, another ALDH inhibitor, did not. DSF, with higher inhibitory activity against FROUNT than DDC and Cu(DDC)2, inhibited monocyte migration most strongly. In BLM-induced fibrotic lung tissues, profibrotic factors were highly expressed but were reduced by DSF treatment. These results suggest DSF inhibits macrophage infiltration, which might be attributed to its inhibitory effect on FROUNT, and attenuates BLM-induced lung fibrosis. In addition, multiplex immunofluorescence imaging revealed reduced infiltration of S100A4+ macrophages into the lungs in DSF-treated mice and high expression of FROUNT in S100A4+ macrophages in idiopathic pulmonary fibrosis (IPF). These findings underscore the potential of macrophage-targeted therapy with DSF as a promising drug repositioning approach for treating fibrotic lung diseases, including IPF.

PMID:39384840 | DOI:10.1038/s41598-024-71770-z

Transl Psychiatry. 2024 Oct 9;14(1):428. doi: 10.1038/s41398-024-03139-9.

ABSTRACT

Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0.05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.

PMID:39384764 | DOI:10.1038/s41398-024-03139-9

Obes Rev. 2024 Oct 9:e13848. doi: 10.1111/obr.13848. Online ahead of print.

ABSTRACT

Obesity is a major public health concern and burden on individuals and healthcare systems. Due to the challenges and limitations of lifestyle adjustments, it is advisable to consider pharmacological treatment for people affected by obesity. However, the side effects and limited efficacy of available drugs make the obesity drug market far from sufficient. Drug repurposing involves identifying new applications for existing drugs and offers some advantages over traditional drug development approaches including lower costs and shorter development timelines. This review aims to provide an overview of drug repurposing for anti-obesity medications, including the rationale for repurposing, the challenges and approaches, and the potential drugs that are being investigated for repurposing. Through advanced computational techniques, researchers can unlock the potential of repurposed drugs to tackle the global obesity epidemic. Further research, clinical trials, and collaborative efforts are essential to fully explore and leverage the potential of drug repurposing in the fight against obesity.

PMID:39384341 | DOI:10.1111/obr.13848

BMC Biol. 2024 Oct 8;22(1):226. doi: 10.1186/s12915-024-02028-3.

ABSTRACT

Drug repurposing is a promising approach in the field of drug discovery owing to its efficiency and cost-effectiveness. Most current drug repurposing models rely on specific datasets for training, which limits their predictive accuracy and scope. The number of both market-approved and experimental drugs is vast, forming an extensive molecular space. Due to limitations in parameter size and data volume, traditional drug-target interaction (DTI) prediction models struggle to generalize well within such a broad space. In contrast, large language models (LLMs), with their vast parameter sizes and extensive training data, demonstrate certain advantages in drug repurposing tasks. In our research, we introduce a novel drug repurposing framework, DrugReAlign, based on LLMs and multi-source prompt techniques, designed to fully exploit the potential of existing drugs efficiently. Leveraging LLMs, the DrugReAlign framework acquires general knowledge about targets and drugs from extensive human knowledge bases, overcoming the data availability limitations of traditional approaches. Furthermore, we collected target summaries and target-drug space interaction data from databases as multi-source prompts, substantially improving LLM performance in drug repurposing. We validated the efficiency and reliability of the proposed framework through molecular docking and DTI datasets. Significantly, our findings suggest a direct correlation between the accuracy of LLMs' target analysis and the quality of prediction outcomes. These findings signify that the proposed framework holds the promise of inaugurating a new paradigm in drug repurposing.

PMID:39379930 | DOI:10.1186/s12915-024-02028-3

Mol Divers. 2024 Oct 9. doi: 10.1007/s11030-024-11003-7. Online ahead of print.

ABSTRACT

The SARS-CoV-2 outbreak highlights the persistent vulnerability of humanity to epidemics and emerging microbial threats, emphasizing the lack of time to develop disease-specific treatments. Therefore, it appears beneficial to utilize existing resources and therapies. Computational drug repositioning is an effective strategy that redirects authorized drugs to new therapeutic purposes. This strategy holds significant promise for newly emerging diseases, as drug discovery is a lengthy and expensive process. Through this study, we present an ensemble method based on the convolutional neural network integrated with genetic algorithm and deep forest classifier for virus-drug association prediction (CGDVDA). We generated feature vectors by combining drug chemical structure and virus genomic sequence-based similarities, and extracted prominent deep features by applying the convolutional neural network. The convoluted features are optimized using the genetic algorithm and classified using the ensemble deep forest classifier to predict novel virus-drug associations. The proposed method predicts drugs for COVID-19 and other viral diseases in the dataset. The model could achieve ROC-AUC scores of 0.9159 on fivefold cross-validation. We compared the performance of the model with state-of-the-art approaches and classifiers. The experimental results and case studies illustrate the efficacy of CGDVDA in predicting drugs against viral infectious diseases.

PMID:39379663 | DOI:10.1007/s11030-024-11003-7

Pharmacol Biochem Behav. 2024 Oct 6:173892. doi: 10.1016/j.pbb.2024.173892. Online ahead of print.

ABSTRACT

Anxiety is a protective behavior when animals face aversive conditions, but commonly associated with various neuropsychiatric disorders when exacerbated. Drug repurposing has emerged as a valuable strategy to use existing pharmaceuticals for new therapeutic purposes. Ketamine, traditionally used as an anesthetic, acts as a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and evidence has shown potential anxiolytic and antidepressant effects at subanesthetic doses. However, the influence of ketamine on multiple behavioral domains in vertebrates is not completely understood. Here, we evaluated the potential modulatory effect of ketamine on the spatio-temporal exploratory dynamics and homebase-related behaviors in adult zebrafish using the open field test (OFT). Animals were exposed to subanesthetic concentrations of ketamine (0, 2, 20, and 40 mg/L) for 20 min and locomotion- exploration- and homebase-related behaviors were assessed in a single 30-min trial. Our data revealed that ketamine (20 and 40 mg/L) induced hyperlocomotion, as verified by the increased total distance traveled. All concentrations tested elicited circling behavior, a stereotyped-like response which gradually reduced across the periods of test. We also observed modulatory effects of ketamine on the spatio-temporal exploratory pattern, in which the reduced thigmotaxis and homebase activity, associated with the increased average length of trips were suggestive of anxiolytic-like effects. Collectively, our novel findings support the modulatory effects of ketamine on the spatio-temporal exploratory activity, as well as the utility of homebase-related measurements to evaluate the behavioral dynamics of zebrafish.

PMID:39378930 | DOI:10.1016/j.pbb.2024.173892

Int J Biol Macromol. 2024 Oct 6:136386. doi: 10.1016/j.ijbiomac.2024.136386. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) remains a highly malignant cancer with a grim prognosis due to its early metastasis and resistance to current chemotherapies, such as Gemcitabine (GEM). We have previously demonstrated that cAMP exclusion by MRP4 is critical for PDAC cell proliferation, establishing this transporter as a promising prognostic marker and therapeutic target. In search for novel therapeutic options to improve GEM efficacy, we conducted a drug repositioning screening to identify potential inhibitors of cAMP transport by MRP4. Several non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the transport of certain MRP4 substrates. In this study, we assessed the efficacy of sixteen NSAIDs in inhibiting cAMP transport mediated by MRP4, identifying seven potent inhibitors based on their IC50 values. The most potent inhibitors were further tested for their effect on cell proliferation and migration. Flurbiprofen emerged as the most potent inhibitor of both MRP4-mediated cAMP transport and cell proliferation. Overexpression of MRP4 in BxPC-3 cells significantly increased GEM resistance, and co-administration of flurbiprofen with GEM markedly enhanced the latter's potency inhibiting PDAC cells proliferation. These findings position flurbiprofen as a potent inhibitor of cAMP transport by MRP4 and a promising adjunctive therapy to enhance GEM effectiveness in PDAC treatment.

PMID:39378921 | DOI:10.1016/j.ijbiomac.2024.136386

Int J Drug Policy. 2024 Oct 7;133:104601. doi: 10.1016/j.drugpo.2024.104601. Online ahead of print.

ABSTRACT

BACKGROUND: In response to the ongoing overdose crisis in Canada, a number of opioid agonist treatment and safer supply programs provide people at high overdose risk with daily-dispensed tablet hydromorphone, with some requiring witnessed ingestion and others providing take-away doses. While these programs are intended to reduce overdose events by limiting people's use of the contaminated drug supply, the experiences of people receiving hydromorphone vary. In this article we explore the ways people repurpose hydromorphone to address unmet needs.

METHODS: This article draws on in-depth qualitative interviews from two studies evaluating hydromorphone tablet distribution programs in British Columbia, Canada. We used thematic analysis to identify themes related to repurposing hydromorphone. We compared themes across the two studies to identify any similarities or differences in relation to the ways study participants discussed repurposing hydromorphone tablets. We utilize vignettes - snapshots of participant experiences - to analyse and represent the data.

RESULTS: Four vignettes demonstrate how hydromorphone tablets are often being used to address and resolve unmet needs of people who use drugs. While most participants reported reducing their use of illicit drugs, a variety of instrumental uses of tablet hydromorphone were also discussed, including reducing anxiety, addressing sleep issues, withdrawal management, and managing chronic pain.

CONCLUSION: Our findings demonstrate how people who use drugs are maximizing the benefits of tablet hydromorphone distribution to address unmet needs. Hydromorphone distribution programs represent a public health and harm reduction intervention that is usefully addressing experiences related to structural vulnerabilities (such as inadequate pain management), which are often overlooked amongst stigmatized groups.

PMID:39378778 | DOI:10.1016/j.drugpo.2024.104601

Microbiol Spectr. 2024 Oct 8:e0013824. doi: 10.1128/spectrum.00138-24. Online ahead of print.

ABSTRACT

While highly effective at killing Gram-positive bacteria, auranofin lacks significant activity against Gram-negative species for reasons that largely remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the low susceptibility of the Gram-negative model organism Escherichia coli to auranofin when compared to the Gram-positive model organism Bacillus subtilis. The proteome response of E. coli exposed to auranofin suggests a combination of inactivation of thiol-containing enzymes and the induction of systemic oxidative stress. Susceptibility tests in E. coli mutants lacking proteins upregulated upon auranofin treatment suggested that none of them are directly involved in E. coli's high tolerance to auranofin. E. coli cells lacking the efflux pump component TolC were more sensitive to auranofin treatment, but not to an extent that would fully explain the observed difference in susceptibility of Gram-positive and Gram-negative organisms. We thus tested whether E. coli's thioredoxin reductase (TrxB) is inherently less sensitive to auranofin than TrxB from B. subtilis, which was not the case. However, E. coli strains lacking the low-molecular-weight thiol glutathione, but not glutathione reductase, showed a high susceptibility to auranofin. Bacterial cells expressing the genetically encoded redox probe roGFP2 allowed us to observe the oxidation of cellular protein thiols in situ. Based on our findings, we hypothesize that auranofin leads to a global disturbance in the cellular thiol redox homeostasis in bacteria, but Gram-negative bacteria are inherently more resistant due to the presence of drug export systems and high cellular concentrations of glutathione.IMPORTANCEAuranofin is an FDA-approved drug for the treatment of rheumatoid arthritis. However, it has also high antibacterial activity, in particular against Gram-positive organisms. In the current antibiotics crisis, this would make it an ideal candidate for drug repurposing. However, its much lower activity against Gram-negative organisms prevents its broad-spectrum application. Here we show that, on the level of the presumed target, there is no difference in susceptibility between Gram-negative and Gram-positive species: thioredoxin reductases from both Escherichia coli and Bacillus subtilis are equally inhibited by auranofin. In both species, auranofin treatment leads to oxidative protein modification on a systemic level, as monitored by proteomics and the genetically encoded redox probe roGFP2. The single largest contributor to E. coli's relative resistance to auranofin seems to be the low-molecular-weight thiol glutathione, which is absent in B. subtilis and other Gram-positive species.

PMID:39377597 | DOI:10.1128/spectrum.00138-24

Sci Rep. 2024 Oct 7;14(1):23297. doi: 10.1038/s41598-024-74243-5.

ABSTRACT

Drug repositioning is gaining attention as a method for developing new drugs due to its low cost, short cycle time, and high success rate. One important approach is to explore new uses for already marketed drugs. In this study, we utilized the strategy of drug repositioning, focusing on the Dan-Lou tablet. We predicted the efficacy of Dan-Lou tablet against non-small cell lung cancer based on gene expression similarity and verified it by in vitro experiments. Next, we performed further analysis and validation using network pharmacology, molecular docking and molecular dynamics. Based on the results, it was concluded that Dan-Lou tablet mainly acted through nine compounds, Quercetin, Luteolin, Scoparone, Isorhamnetin, Eugenol, Genistein, Coumestrol, Hederagenin, Succinic Acid, and mainly targeted CCL2, FEN1, TPI1, RMI2 by six pathways. This discovery not only provides a new idea for the development of Dan-Lou tablet but also provides useful predictive information for clinical treatment. The method we adopted has great development prospects as a way to predict the efficacy of new drugs and their main mechanisms of action, and it has a positive impact on the research and development of new drugs using drug repositioning and the modernization of traditional Chinese medicine.

PMID:39375410 | DOI:10.1038/s41598-024-74243-5

Microb Pathog. 2024 Oct 5:106993. doi: 10.1016/j.micpath.2024.106993. Online ahead of print.

ABSTRACT

Otitis externa is an inflammatory disease of the external ear canal of complex and multifactorial etiology associated with recurrent bacterial infection. This study aimed to assess the antimicrobial and antibiofilm activity of promethazine against bacterial isolates from dogs with otitis externa, as well as the effect of this compound on the dynamics of biofilm formation over 120 hours. Planktonic bacterial susceptibility to promethazine was evaluated to determine the minimum inhibitory concentrations (MIC). The minimum biofilm eradication concentration (MBEC) was also determined by broth microdilution. To evaluate the effect on biofilm growth, promethazine was tested at three concentrations MIC, MIC/2 and MIC/8, with daily readings at 48, 72, 96 and 120 h. The MICs of promethazine ranged from 48.83 to 781.25 μg mL-1. Promethazine significantly (P<0.05) reduced mature biofilm biomass, with MBECs ranging from 48.8 to 6250 μg mL-1 and reduced (P<0.01) biofilm formation for up to the 120-hours, at concentrations corresponding to the MIC obtained against each isolate. Promethazine was effective against microorganisms associated with canine otitis externa. The data suggest that promethazine presents antimicrobial and antibiofilm activity and is a potential alternative to treat and prevent recurrent bacterial otitis in dogs. These results emphasize the importance of drug repurposing in veterinary otology as an alternative to reduce antimicrobial resistance.

PMID:39374884 | DOI:10.1016/j.micpath.2024.106993

Blood Adv. 2024 Oct 7:bloodadvances.2024013810. doi: 10.1182/bloodadvances.2024013810. Online ahead of print.

ABSTRACT

Platelet clot retraction, the ultimate phase of platelet thrombus formation, is critical for clot stabilization. It requires functional αIIbβ3 receptors, fibrin, and the integrated actions of the actin-myosin contractile and cytoskeletal systems. Disturbances in clot retraction have been associated with both bleeding and thrombosis. We recently demonstrated that platelets treated with the αIIbβ3 antagonist peptide RGDW, which eliminates fibrinogen-mediated platelet aggregation, are still able to retract clots. We have exploited this observation to developed an unbiased, functional high-throughput assay to identify small molecule inhibitors of fibrin-mediated clot retraction adapted for a 384-well plate format. We tested 9,710 compounds from drug-repurposing libraries (DRL's). These libraries contain compounds that are either FDA-approved or have undergone preclinical/clinical development. We identified 27 compounds from the LOPAC library as inhibitors of clot retraction of which 14 are known inhibitors of platelet function. From the DRL we identified 135 compounds (1.6% hit rate). After extensive curation, these compounds were categorized based on the activity of their reported target. Multiple kinase and phosphodiesterase inhibitors with known antiplatelet effects were identified, along with multiple deubiquitination and receptor inhibitors, as well as compounds that have not previously been reported to have antiplatelet activity. Studies of one of the deubiquitination inhibitors (degrasyn) suggests that its effects are downstream of platelet-fibrinogen interactions and thus may permit the separation of platelet aggregation-mediated events from clot retraction. Additional studies of the identified compounds may lead to novel mechanisms of inhibiting thrombosis.

PMID:39374578 | DOI:10.1182/bloodadvances.2024013810

FASEB J. 2024 Oct 15;38(19):e70083. doi: 10.1096/fj.202401254R.

ABSTRACT

Drug-target binding affinity (DTA) prediction is vital for drug repositioning. The accuracy and generalizability of DTA models remain a major challenge. Here, we develop a model composed of BERT-Trans Block, Multi-Trans Block, and DTI Learning modules, referred to as Molecular Representation Encoder-based DTA prediction (MREDTA). MREDTA has three advantages: (1) extraction of both local and global molecular features simultaneously through skip connections; (2) improved sensitivity to molecular structures through the Multi-Trans Block; (3) enhanced generalizability through the introduction of BERT. Compared with 12 advanced models, benchmark testing of KIBA and Davis datasets demonstrated optimal performance of MREDTA. In case study, we applied MREDTA to 2034 FDA-approved drugs for treating non-small-cell lung cancer (NSCLC), all of which act on mutant EGFRT790M protein. The corresponding molecular docking results demonstrated the robustness of MREDTA.

PMID:39373982 | DOI:10.1096/fj.202401254R

Mol Biotechnol. 2024 Oct 7. doi: 10.1007/s12033-024-01296-2. Online ahead of print.

ABSTRACT

Niclosamide has emerged as a promising repurposed drug against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro studies suggested that niclosamide inhibits the host transmembrane protein 16F (hTMEM16F), crucial for lipid scramblase activity, which consequently reduces syncytia formation that aids viral spread. Based on other in vitro reports, niclosamide may also target viral proteases such as papain-like protease (PLpro) and main protease (Mpro), essential for viral replication and maturation. However, the precise interactions by which niclosamide interacts with these multiple targets remain largely unclear. Docking and molecular dynamics (MD) simulation studies were undertaken based on a homology model of the hTMEM16F and available crystal structures of SARS-CoV-2 PLpro and Mpro. Niclosamide was observed to bind stably throughout a 400 ns MD simulation at the extracellular exit gate of the hTMEM16F tunnel, forming crucial interactions with residues spanning the TM1-TM2 loop (Gln350), TM3 (Phe481), and TM5-TM6 loop (Lys573, Glu594, and Asp596). Among the SARS-CoV-2 proteases, niclosamide was found to interact effectively with conserved active site residues of PLpro (Tyr268), exhibiting better stability in comparison to the control inhibitor, GRL0617. In conclusion, our in silico analyses support niclosamide as a multi-targeted drug inhibiting viral and host proteins involved in SARS-CoV-2 infections.

PMID:39373955 | DOI:10.1007/s12033-024-01296-2

RSC Med Chem. 2024 Sep 16. doi: 10.1039/d4md00461b. Online ahead of print.

ABSTRACT

In the quest to identify new anti-Alzheimer agents, we employed drug repositioning or drug repositioning techniques on approved USFDA small molecules. Herein, we report the structure-based virtual screening (SBVS) of 1880 USFDA-approved drugs. The in silico-based identification was followed by calculating Prime MMGB-SA binding energy and molecular dynamics simulation studies. The cumulative analysis led to identifying domperidone as an identified hit. Domperidone was further corroborated in vitro using anticholinesterase-based assessment, keeping donepezil as a positive control. The analysis revealed that the identified lead (domperidone) could induce an inhibitory effect on AChE in a dose-dependent manner with an IC50 of 3.67 μM as compared to donepezil, which exhibited an IC50 of 1.37 μM. However, as domperidone is known to have poor BBB permeability, we rationally proposed new analogues utilizing the principles of bioisosterism. The bioisostere-clubbed analogues were found to have better BBB permeability, affinity, and stability within the catalytic domain of AChE via molecular docking and dynamics studies. The proposed bioisosteres may be synthesized in the future. They may plausibly be explored for their implication in the developmental progress of new anti-Alzheimer agent achieved via repurposing techniques in future.

PMID:39371435 | PMC:PMC11447705 | DOI:10.1039/d4md00461b

Reprod Toxicol. 2024 Oct 4:108730. doi: 10.1016/j.reprotox.2024.108730. Online ahead of print.

ABSTRACT

A strong link between antipsychotic drug use and reduced human sperm quality has been reported. Trifluoperazine (TFP), a commonly used antipsychotic, is now being explored for anticancer applications. Although there are hints that TFP might affect the male reproductive system, its impact on human sperm quality remains uncertain. Using a human sperm and TFP in vitro coculture system, we examined the effect of TFP (12.5, 25, 50 and 100μM) on human sperm function and physiological parameters. The results showed that 50μM and 100μM TFP induced the accumulation of reactive oxygen species (ROS) and a decrease in the mitochondrial membrane potential (MMP) of human sperm, leading to decreased sperm viability, while 25μM TFP inhibited only the penetration ability, total sperm motility, and progressive motility. Although 12.5μM and 25μM TFP increased [Ca2+]i in human sperm, they did not affect capacitation or the acrosome reaction. These results may be explained by the observation that 12.5μM and 25μM TFP did not increase tyrosine phosphorylation in human sperm, although TFP increased [Ca2+]i in a time-course traces similar to that of progesterone. Our results indicated that TFP could cause male reproductive toxicity by inducing the accumulation of ROS and a decrease in the MMP in human sperm.

PMID:39369966 | DOI:10.1016/j.reprotox.2024.108730