Bioinformatics. 2024 Aug 8:btae496. doi: 10.1093/bioinformatics/btae496. Online ahead of print.

ABSTRACT

MOTIVATION: Drug-target interactions (DTIs) hold a pivotal role in drug repurposing and elucidation of drug mechanisms of action. While single-targeted drugs have demonstrated clinical success, they often exhibit limited efficacy against complex diseases, such as cancers, whose development and treatment is dependent on several biological processes. Therefore, a comprehensive understanding of primary, secondary and even inactive targets becomes essential in the quest for effective and safe treatments for cancer and other indications. The human proteome offers over a thousand druggable targets, yet most FDA-approved drugs bind to only a small fraction of these targets.

RESULTS: This study introduces an attention-based method (called as MMAtt-DTA) to predict drug-target bioactivities across human proteins within seven superfamilies. We meticulously examined nine different descriptor sets to identify optimal signature descriptors for predicting novel DTIs. Our testing results demonstrated Spearman correlations exceeding 0.72 (P < 0.001) for six out of seven superfamilies. The proposed method outperformed fourteen state-of-the-art machine learning, deep learning and graph-based methods and maintained relatively high performance for most target superfamilies when tested with independent bioactivity data sources. We computationally validated 185,676 drug-target pairs from ChEMBL-V33 that were not available during model training, achieving a reasonable performance with Spearman correlation greater than 0.57 (P < 0.001) for most superfamilies. This underscores the robustness of the proposed method for predicting novel DTIs. Finally, we applied our method to predict missing bioactivities among 3,492 approved molecules in ChEMBL-V33, offering a valuable tool for advancing drug mechanism discovery and repurposing existing drugs for new indications.

AVAILABILITY: https://github.com/AronSchulman/MMAtt-DTA.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:39115379 | DOI:10.1093/bioinformatics/btae496

Arch Biochem Biophys. 2024 Aug 5:110111. doi: 10.1016/j.abb.2024.110111. Online ahead of print.

ABSTRACT

Chikungunya virus (CHIKV), transmitted by mosquitoes, poses a significant global health threat. Presently, no effective treatment options are available to reduce the disease burden. The lack of approved therapeutics against CHIKV and the complex spectrum of chronic musculoskeletal and neurological manifestations raise significant concerns, and repurposing drugs could offer swift avenues in the development of effective treatment strategies. RNA capping is a crucial step meditated by non-structural protein 1 (nsP1) in CHIKV replication. In this study, FDA-approved antivirals targeting CHIKV nsP1 methyltransferase (MTase) have been identified by structure-based virtual screening. Berbamine Hydrochloride (BH), ABT199/Venetoclax (ABT), and Ponatinib (PT) were the top hits, which exhibited robust binding energies. Tryptophan fluorescence spectroscopy-based assay confirmed binding of BH-, ABT-, and PT to purified nsP1 with KD values ∼5.45 μM, ∼161.3 μM, and ∼3.83μM, respectively. In a capillary electrophoresis-based assay, a decrease in CHIKV nsP1 MTase activity was observed in a dose-dependent manner. Treatment with BH, ABT, and PT lead to a dose-dependent reduction in the virus titer with IC50 <100, ∼6.75, and <3.9 nM, respectively, and reduced viral mRNA levels. The nsP1 MTases are highly conserved among alphaviruses; therefore, BH, ABT, and PT, as expected, inhibited replication machinery in Sindbis virus (SINV) replicon assay with IC50 ∼1.94, ∼0.23, and >1.25 μM, respectively. These results underscore the efficacy and promise of repurposing drugs as rapid and effective antiviral therapeutics against CHIKV.

PMID:39111614 | DOI:10.1016/j.abb.2024.110111

J Chem Inf Model. 2024 Aug 7. doi: 10.1021/acs.jcim.4c00718. Online ahead of print.

ABSTRACT

Thrombocytopenia, which is associated with thrombopoietin (TPO) deficiency, presents very limited treatment options and can lead to life-threatening complications. Discovering new therapeutic agents against thrombocytopenia has proven to be a challenging task using traditional screening approaches. Fortunately, machine learning (ML) techniques offer a rapid avenue for exploring chemical space, thereby increasing the likelihood of uncovering new drug candidates. In this study, we focused on computational modeling for drug-induced megakaryocyte differentiation and platelet production using ML methods, aiming to gain insights into the structural characteristics of hematopoietic activity. We developed 112 different classifiers by combining eight ML algorithms with 14 molecule features. The top-performing model achieved good results on both 5-fold cross-validation (with an accuracy of 81.6% and MCC value of 0.589) and external validation (with an accuracy of 83.1% and MCC value of 0.642). Additionally, by leveraging the Shapley additive explanations method, the best model provided quantitative assessments of molecular properties and structures that significantly contributed to the predictions. Furthermore, we employed an ensemble strategy to integrate predictions from multiple models and performed in silico predictions for new molecules with potential activity against thrombocytopenia, sourced from traditional Chinese medicine and the Drug Repurposing Hub. The findings of this study could offer valuable insights into the structural characteristics and computational prediction of thrombopoiesis inducers.

PMID:39109515 | DOI:10.1021/acs.jcim.4c00718

Curr Comput Aided Drug Des. 2024 Aug 6. doi: 10.2174/0115734099326517240801035901. Online ahead of print.

NO ABSTRACT

PMID:39108125 | DOI:10.2174/0115734099326517240801035901

Biol Sex Differ. 2024 Aug 6;15(1):62. doi: 10.1186/s13293-024-00634-y.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) has been observed to have significant sex differences in incidence, prognosis, and response to therapy. However, the molecular mechanisms responsible for these disparities have not been investigated extensively.

METHODS: Sample-specific gene regulatory network methods were used to analyze RNA sequencing data from non-cancerous human lung samples from The Genotype Tissue Expression Project (GTEx) and lung adenocarcinoma primary tumor samples from The Cancer Genome Atlas (TCGA); results were validated on independent data.

RESULTS: We found that genes associated with key biological pathways including cell proliferation, immune response and drug metabolism are differentially regulated between males and females in both healthy lung tissue and tumor, and that these regulatory differences are further perturbed by tobacco smoking. We also discovered significant sex bias in transcription factor targeting patterns of clinically actionable oncogenes and tumor suppressor genes, including AKT2 and KRAS. Using differentially regulated genes between healthy and tumor samples in conjunction with a drug repurposing tool, we identified several small-molecule drugs that might have sex-biased efficacy as cancer therapeutics and further validated this observation using an independent cell line database.

CONCLUSIONS: These findings underscore the importance of including sex as a biological variable and considering gene regulatory processes in developing strategies for disease prevention and management.

PMID:39107837 | DOI:10.1186/s13293-024-00634-y

Med Oncol. 2024 Aug 6;41(9):219. doi: 10.1007/s12032-024-02461-y.

ABSTRACT

Bladder cancer is a common malignancy worldwide, posing a substantial healthcare challenge. Current standard treatment regimens are primarily based on cisplatin, but their success is often limited by cisplatin resistance and associated toxicities. Therefore, there is an urgent need to develop effective and less toxic therapies as alternatives to cisplatin. We screened the activity of FDA-approved anti-cancer drugs on a panel of cisplatin-resistant bladder cancer cell lines. Based on initial responses, cabazitaxel was selected for further evaluation of its inhibitory effects on the phenotypic properties of these cells. Cabazitaxel, primarily used for metastatic castration-resistant prostate cancer, demonstrated remarkable efficacy in inhibiting colony formation, proliferation, and migration of cisplatin-resistant bladder cancer cells. This study highlights the potential of drug repurposing as a cost-effective and efficient strategy to overcome drug resistance in bladder cancer.

PMID:39105986 | DOI:10.1007/s12032-024-02461-y

Front Pharmacol. 2024 Jul 22;15:1411285. doi: 10.3389/fphar.2024.1411285. eCollection 2024.

ABSTRACT

INTRODUCTION: Romosozumab is a monoclonal antibody approved for osteoporosis which targets sclerostin, an endogenous inhibitor of Wnt/β-catenin pathway. Given the essential roles of the Wnt/β-catenin pathway in various tissues, we hypothesized romosozumab treatment may influence other conditions.

METHODS: This cohort study included patients prescribed romosozumab or parathyroid receptor (PTHR) agonists after 1 January 2019, using a Japanese electronic medical record database. The outcomes of interest included autoimmune disease, interstitial pneumonia, cardiovascular outcome, Alzheimer's disease, Parkinson's disease (PD), serious infections, and malignancies. A stabilized inverse probability-weighted Cox proportional hazard model was used to estimate the hazard ratios. Age- and gender-based subgroup analyses were conducted. Exploratory outcomes based on three-digit International Classification of Diseases 10th Revision-based were also examined.

RESULTS: In total, 2,673 patients treated with romosozumab and 5,980 treated with PTHR agonists were identified, respectively. While most outcomes of interest showed no association with romosozumab, the risk of PD decreased with romosozumab (hazard ratio [95% confidence interval], 0.37 [0.14-0.94]) compared with PTHR agonist. Regarding the cardiovascular outcome, no notable association was identified overall; however, gender-based subgroup analysis suggested that male sex may be a potential risk factor with romosozumab treatment. Only 16 of 903 exploratory outcomes were potentially influenced by romosozumab.

CONCLUSION: Romosozumab lowered the risk of PD development compared with PTHR agonist. The study also highlights the utility of routinely collected health data for drug repositioning. While further validation is warranted, the findings suggest that the Wnt-β-catenin pathway holds promise as a therapeutic target for PD.

PMID:39104397 | PMC:PMC11298754 | DOI:10.3389/fphar.2024.1411285

Hum Genet. 2024 Aug 6. doi: 10.1007/s00439-024-02696-9. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease accompanied by both local and systemic comorbidities. Genetic factors play a role in the development of IPF and certain associated comorbidities. Nevertheless, it is uncertain whether there are shared genetic factors underlying IPF and these comorbidities. To bridge this knowledge gap, we conducted a systematic investigation into the shared genetic architecture between IPF and ten prevalent heritable comorbidities (i.e., body mass index [BMI], coronary artery disease [CAD], chronic obstructive pulmonary disease [COPD], gastroesophageal reflux disease, lung cancer, major depressive disorder [MDD], obstructive sleep apnoea, pulmonary hypertension [PH], stroke, and type 2 diabetes), by utilizing large-scale summary data from their respective genome-wide association studies and multi-omics studies. We revealed significant (false discovery rate [FDR] < 0.05) and moderate genetic correlations between IPF and seven comorbidities, excluding lung cancer, MDD and PH. Evidence suggested a partially putative causal effect of IPF on CAD. Notably, we observed FDR-significant genetic enrichments in lung for the cross-trait between IPF and CAD and in liver for the cross-trait between IPF and COPD. Additionally, we identified 65 FDR-significant genes over-represented in 20 biological pathways related to the etiology of IPF, BMI, and COPD, including inflammation-related mucin gene clusters. Several of these genes were associated with clinically relevant drugs for the treatment of IPF, CAD, and/or COPD. Our results underscore the pervasive shared genetic basis between IPF and its common comorbidities and hold future implications for early diagnosis of IPF-related comorbidities, drug repurposing, and the development of novel therapies for IPF.

PMID:39103522 | DOI:10.1007/s00439-024-02696-9

ChemistryOpen. 2024 Aug 5:e202400091. doi: 10.1002/open.202400091. Online ahead of print.

ABSTRACT

The emergence of drug-resistant viruses and novel strains necessitates the rapid development of novel antiviral therapies. This need was particularly demanding during the COVID-19 pandemic. While de novo drug development is a time-consuming process, repurposing existing approved medications offers a more expedient approach. In our prior in silico screening of the DrugBank database, fidaxomicin emerged as a potential SARS-CoV-2 papain-like protease inhibitor. This study extends those findings by investigating fidaxomicin's antiviral properties in vitro. Our results support further exploration of fidaxomicin as a therapeutic candidate against SARS-CoV-2, given its promising in vitro antiviral activity and favorable safety profile.

PMID:39099532 | DOI:10.1002/open.202400091

Cell Signal. 2024 Aug 2:111329. doi: 10.1016/j.cellsig.2024.111329. Online ahead of print.

ABSTRACT

Mitochondria, traditionally known as cellular powerhouses, now emerge as critical signaling centers influencing cancer progression and drug resistance. The review highlights the role that apoptotic signaling, DNA mutations, mitochondrial dynamics and metabolism play in the development of resistance mechanisms and the advancement of cancer. Targeted approaches are discussed, with an emphasis on managing mitophagy, fusion, and fission of the mitochondria to make resistant cancer cells more susceptible to traditional treatments. Additionally, metabolic reprogramming can be used to effectively target metabolic enzymes such GLUT1, HKII, PDK, and PKM2 in order to avoid resistance mechanisms. Although there are potential possibilities for therapy, the complex structure of mitochondria and their subtle role in tumor development hamper clinical translation. Novel targeted medicines are put forth, providing fresh insights on combating drug resistance in cancer. The study also emphasizes the significance of glutamine metabolism, mitochondrial respiratory complexes, and apoptotic pathways as potential targets to improve treatment effectiveness against drug-resistant cancers. Combining complementary and nanoparticle-based techniques to target mitochondria has demonstrated encouraging results in the treatment of cancer, opening doors to reduce resistance and enable individualized treatment plans catered to the unique characteristics of each patient. Suggesting innovative approaches such as drug repositioning and mitochondrial drug delivery to enhance the efficacy of mitochondria-targeting therapies, presenting a pathway for advancements in cancer treatment. This thorough investigation is a major step forward in the treatment of cancer and has the potential to influence clinical practice and enhance patient outcomes.

PMID:39098704 | DOI:10.1016/j.cellsig.2024.111329

Cell Genom. 2024 Jul 29:100627. doi: 10.1016/j.xgen.2024.100627. Online ahead of print.

ABSTRACT

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

PMID:39096913 | DOI:10.1016/j.xgen.2024.100627

Mol Genet Metab. 2024 Jul 17;143(1-2):108538. doi: 10.1016/j.ymgme.2024.108538. Online ahead of print.

ABSTRACT

Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent congenital disorder of glycosylation, is an autosomal recessive disease caused by biallelic pathogenic variants in the PMM2 gene. There is no cure for this multisystemic syndrome. Some of the therapeutic approaches that are currently in development include mannose-1-phosphate replacement therapy, drug repurposing, and the use of small chemical molecules to correct folding defects. Preclinical models are needed to evaluate the efficacy of treatments to overcome the high lethality of the available animal model. In addition, the number of variants with unknown significance is increasing in clinical settings. This study presents the generation of a cellular disease model by knocking out the PMM2 gene in the hepatoma HepG2 cell line using CRISPR-Cas9 gene editing. The HepG2 knockout model accurately replicates the PMM2-CDG phenotype, exhibiting a complete absence of PMM2 protein and mRNA, a 90% decrease in PMM enzymatic activity, and altered ICAM-1, LAMP1 and A1AT glycoprotein patterns. The evaluation of PMM2 disease-causing variants validates the model's utility for studying new PMM2 clinical variants, providing insights for diagnosis and potentially for evaluating therapies. A CRISPR-Cas9-generated HepG2 knockout model accurately recapitulates the PMM2-CDG phenotype, providing a valuable tool for assessing disease-causing variants and advancing therapeutic strategies.

PMID:39096554 | DOI:10.1016/j.ymgme.2024.108538

ACS Chem Neurosci. 2024 Aug 3. doi: 10.1021/acschemneuro.4c00150. Online ahead of print.

ABSTRACT

The misfolding and aggregation of beta-amyloid (Aβ) peptides have been implicated as key pathogenic events in the early stages of Alzheimer's disease (AD). Inhibiting Aβ aggregation represents a potential disease-modifying therapeutic approach to AD treatment. Previous studies have identified various molecules that inhibit Aβ aggregation, some of which share common chemical substructures (fragments) that may be key to their inhibitory activity. Employing fragment-based drug discovery (FBDD) methods may facilitate the identification of these fragments, which can subsequently be used to screen new inhibitors and provide leads for further drug development. In this study, we used an in silico FBDD approach to identify 17 fragment clusters that are significantly enriched among Aβ aggregation inhibitors. These fragments were then used to screen anti-infective agents, a promising drug class for repurposing against amyloid aggregation. This screening process identified 16 anti-infective drugs, 5 of which were chosen for further investigation. Among the 5 candidates, anidulafungin, an antifungal compound, showed high efficacy in inhibiting Aβ aggregation in vitro. Kinetic analysis revealed that anidulafungin selectively blocks the primary nucleation step of Aβ aggregation, substantially delaying Aβ fibril formation. Cell viability assays demonstrated that anidulafungin can reduce the toxicity of oligomeric Aβ on BV2 microglia cells. Molecular docking simulations predicted that anidulafungin interacted with various Aβ species, including monomers, oligomers, and fibrils, potentially explaining its activity against Aβ aggregation and toxicity. This study suggests that anidulafungin is a potential drug to be repurposed for AD, and FBDD is a promising approach for discovering drugs to combat Aβ aggregation.

PMID:39096284 | DOI:10.1021/acschemneuro.4c00150

Viral Immunol. 2024 Aug 5. doi: 10.1089/vim.2024.0034. Online ahead of print.

ABSTRACT

The COVID-19 pandemic response has been hindered by the absence of an efficient antiviral therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The reason why the previous preventative approach to COVID-19 solely through vaccines has failed could be a lack of understanding of how quickly the SARS-CoV-2 virus evolves. Given the absence of specific treatments for the virus, efforts have been underway to explore treatment options. Drug repurposing involves identifying new therapeutic uses for approved drugs, proving to be a time-saving strategy with minimal risk of failure. In this study, we report the successful use of a multidrug approach in patients with COVID-19. Successful administration of multidrug therapy, such as combinations of hydroxychloroquine and azithromycin, doxycycline and ivermectin, or ivermectin, doxycycline, and azithromycin, has been reported. Multidrug therapy is effective because of the differing mechanisms of action of these drugs, and it may also mitigate the emergence of drug-resistant SARS-CoV-2 strains. The medicines were lopinavir/ritonavir (Kaletra), bamlanivimab (monoclonal antibody), glycopyrrolate-formoterol (Bevespi), ciclesonide (Alvesco), famotidine (Pepcid), and diphenhydramine (Benadryl).

PMID:39096169 | DOI:10.1089/vim.2024.0034

DNA Repair (Amst). 2024 Jul 25;141:103732. doi: 10.1016/j.dnarep.2024.103732. Online ahead of print.

ABSTRACT

The human DNA repair enzyme AlkB homologue-2 (ALKBH2) repairs methyl adducts from genomic DNA and is overexpressed in several cancers. However, there are no known inhibitors available for this crucial DNA repair enzyme. The aim of this study was to examine whether the first-generation HIV protease inhibitors having strong anti-cancer activity can be repurposed as inhibitors of ALKBH2. We selected four such inhibitors and performed in vitro binding analysis against ALKBH2 based on alterations of its intrinsic tryptophan fluorescence and differential scanning fluorimetry. The effect of these HIV protease inhibitors on the DNA repair activity of ALKBH2 was also evaluated. Interestingly, we observed that one of the inhibitors, ritonavir, could inhibit ALKBH2-mediated DNA repair significantly via competitive inhibition and sensitized cancer cells to alkylating agent methylmethane sulfonate (MMS). This work may provide new insights into the possibilities of utilizing HIV protease inhibitor ritonavir as a DNA repair antagonist.

PMID:39094381 | DOI:10.1016/j.dnarep.2024.103732

Medicine (Baltimore). 2024 Aug 2;103(31):e39138. doi: 10.1097/MD.0000000000039138.

ABSTRACT

Xianlinggubao formula (XLGB), is a traditional Chinese compound Medicine that has been extensively used in osteoarthritis and aseptic osteonecrosis, but its curative effect on diabetic osteoporosis (DOP) and its pharmacological mechanisms remains not clear. The aim of the present study was to investigate the possible mechanism of drug repurposing of XLGB in DOP therapy. We acquired XLGB active compounds from the traditional Chinese medicine systems pharmacology and traditional Chinese medicines integrated databases and discovered potential targets for these compounds by conducting target fishing using the traditional Chinese medicine systems pharmacology and Swiss Target Prediction databases. Gene Cards and Online Mendelian Inheritance in Man® database were used to identify the DOP targets. Overlapping related targets between XLGB and DOP was selected to build a protein-protein interaction network. Next, the Metascape database was utilized to enrich the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. In addition, Auto-Dock Vina software was used to verify drug and target binding. In total, 48 hub targets were obtained as the candidate targets responsible for DOP therapy. The anti-DOP effect mediated by XLGB was primarily centralized on the advanced glycation end products (AGEs)-receptor for AGE signaling pathway in diabetic complications and osteoclast differentiation. In addition, AKT serine/threonine kinase 1, tumor necrosis factor, Interleukin-6, vascular endothelial growth factor A and peroxisome proliferator activated receptor gamma, which were considered as potential therapeutic targets. Furthermore, molecular docking results confirm the credibility of the predicted therapeutic targets. This study elucidates that XLGB may through regulating AGEs formation and osteoclast differentiation as well as angiogenesis and adipogenesis against DOP. And this study provides new promising points to find the exact regulatory mechanisms of XLGB mediated anti-DOP effect.

PMID:39093780 | DOI:10.1097/MD.0000000000039138

J Proteome Res. 2024 Aug 2. doi: 10.1021/acs.jproteome.4c00044. Online ahead of print.

ABSTRACT

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

PMID:39093603 | DOI:10.1021/acs.jproteome.4c00044

Front Pharmacol. 2024 Jul 18;15:1419110. doi: 10.3389/fphar.2024.1419110. eCollection 2024.

ABSTRACT

Medicinal polypharmacology is one answer to the complex reality of multifactorial human diseases that are often unresponsive to single-targeted treatment. It is an admittance that intrinsic feedback mechanisms, crosstalk, and disease networks necessitate drugs with broad modes-of-action and multitarget affinities. Medicinal polypharmacology grew to be an independent research field within the last two decades and stretches from basic drug development to clinical research. It has developed its own terminology embedded in general terms of pharmaceutical drug discovery and development at the intersection of medicinal chemistry, chemical biology, and clinical pharmacology. A clear and precise language of critical terms and a thorough understanding of underlying concepts is imperative; however, no comprehensive work exists to this date that could support researchers in this and adjacent research fields. In order to explore novel options, establish interdisciplinary collaborations, and generate high-quality research outputs, the present work provides a first-in-field glossary to clarify the numerous terms that have originated from various individual disciplines.

PMID:39092220 | PMC:PMC11292611 | DOI:10.3389/fphar.2024.1419110

bioRxiv [Preprint]. 2024 Jul 22:2024.07.20.602911. doi: 10.1101/2024.07.20.602911.

ABSTRACT

Adverse drug reactions (ADRs) are a major concern in clinical healthcare, significantly affecting patient safety and drug development. The need for a deeper understanding of ADR mechanisms is crucial for improving drug safety profiles in drug design and drug repurposing. This study introduces DREAMER (Drug adverse REAction Mechanism ExplaineR), a novel network-based method for exploring the mechanisms underlying adverse drug reactions and disease phenotypes at a molecular level by leveraging a comprehensive knowledge graph obtained from various datasets. By considering drugs and diseases that cause similar phenotypes, and investigating their commonalities regarding their impact on specific modules of the protein-protein interaction network, DREAMER can robustly identify protein sets associated with the biological mechanisms underlying ADRs and unravel the causal relationships that contribute to the observed clinical outcomes. Applying DREAMER to 649 ADRs, we identified proteins associated with the mechanism of action for 67 ADRs across multiple organ systems, e.g., ventricular arrhythmia, metabolic acidosis, and interstitial pneumonitis. In particular, DREAMER highlights the importance of GABAergic signaling and proteins of the coagulation pathways for personality disorders and intracranial hemorrhage, respectively. We further demonstrate the application of DREAMER in drug repurposing and propose sotalol (targeting KCNH2), ranolazine (targeting SCN5A, currently under clinical trial), and diltiazem (indicated drug targeting CACNA1C and SCN3A) as candidate drugs to be repurposed for cardiac arrest. In summary, DREAMER effectively detects molecular mechanisms underlying phenotypes emphasizing the importance of network-based analyses with integrative data for enhancing drug safety and accelerating the discovery of novel therapeutic strategies.

PMID:39091742 | PMC:PMC11291051 | DOI:10.1101/2024.07.20.602911

Dermatol Ther (Heidelb). 2024 Aug 2. doi: 10.1007/s13555-024-01227-8. Online ahead of print.

ABSTRACT

Epidermolysis bullosa (EB) comprises rare genetic disorders characterized by skin and mucosal membrane blistering induced by mechanical trauma. Molecularly, pathogenic variants affect genes encoding proteins crucial for epidermal-dermal adhesion and stability. Management of severe EB is multidisciplinary, focusing on wound healing support, ensuring that patients thrive, and complication treatment. Despite extensive research over 30 years, novel therapeutic approaches face challenges. Gene therapy and protein therapy struggle with efficacy, while regenerative cell-based therapies show limited effects. Drug repurposing to target various pathogenic mechanisms has gained attention, as has in vivo gene therapy with drugs for dystrophic and junctional EB that were recently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). However, their high cost limits global accessibility. This review examines therapeutic advancements made over the past 5 years, exploiting a systematic literature review and clinical trial data.

PMID:39090514 | DOI:10.1007/s13555-024-01227-8