Drug Targets Research Articles

In silico discovery of druggable targets in Citrobacter koseri using echinoderm metabolites and molecular dynamics simulation

Citrobacter koseri causes infection in people who are immunocompromised. Without effective antibiotics, these infections can become severe and life-threatening, so effective drugs are essential to treat these infections. Utilizing subtractive genomics, 2699 ORFs were predicted and translated into amino acid sequences. Metabolic pathway analysis and subcellular localization helped define the roles of key bacterial proteins. Two druggable proteins, WP_012000829.1 and WP_275157394.1, were discovered as promising targets. Alpha Fold provided 3D structures, and a library of 1600 echinoderm metabolites was docked against these proteins, with Ampicillin, Levofloxacin, and Doxycycline as controls. Notably, CMNPD13085 and CMNPD15632 exhibited the highest binding affinities for WP_012000829.1 and WP_275157394.1, respectively. Molecular dynamics simulations and MM-GBSA binding free energy complemented docking results. However, acknowledging the reliance on computational validations, the study emphasizes the need for essential in-vitro research to transform these potential inhibitors into therapeutic drugs.

Low nucleotide diversity of the Plasmodium falciparum AP2-EXP2 gene among clinical samples from Ghana.

PfAP2-EXP2 is located within chromosome 6 of Plasmodium falciparum recently identified to be undergoing an extensive selective sweep in West African isolates. The gene encoding this transcription factor, PfAP2-EXP2, is essential and thus likely subject to purifying selection that limits variants in the parasite population despite its genomic location. 72 Plasmodium falciparum field samples and 801 clinical sequences from the Pf6 MalariaGEN dataset of Ghanaian origin, were integrated and analysed. A total of 14 single nucleotide variants of which 5 were missense variants, were identified after quality checks and filtering. Except for one, all identified variants were rare among the clinical samples obtained in this study (Minor allelic frequency < 0.01). Further results revealed a considerably low dN/dS value (0.208) suggesting the presence of purifying selection. Further, all the mutant amino acids were wildtype residues in AP2-EXP2 orthologous proteins-tentatively suggesting a genus-level conservation of amino acid residues. Computational analysis and predictions corroborated these findings. Despite the recent extensive selective sweep within chromosome 6 of West African isolates, PfAP2-EXP2 of Ghanaian origin exhibits low nucleotide diversity and very low dN/dS consistent with purifying selection acting to maintain the function of an essential gene. The conservation of AP2-EXP2 is an important factor that makes it a potential drug target.

Exploring bacterial metabolites in microbe-human host dialogue and their therapeutic potential in Alzheimer's diseases.

Neurological dysfunction in association with aging, dementia, and cognitive impairment is the major cause of Alzheimer's disease (AD). Current AD therapies often yield unsatisfactory results due to their poor mechanism in treating the underlying mechanism of the disease. Recent studies suggested that metabolites from the gut microbiota facilitate brain-gut communication. A systematic network pharmacology study and the structure- and analog-based approaches are employed to investigate the metabolites produced by gut microbiota to treat AD. The microbiota metabolites available in the gutMGene database were considered in this study. Two servers, namely Swiss Target Prediction (STP) and Similarity Ensemble Approach (SEA), were used to identify the possible AD targets for the selected metabolites. Detailed KEGG pathway and Gene Ontology (GO) analysis on identified hub genes highlighted the importance of IL6, AKT1, and GSK3B in AD pathophysiology. MMTSp (Microbiota Metabolites Target Signaling pathways) network analysis elucidated that there is a strong relationship with microbiota (Paraprevotella xylaniphila YIT 11841, Bifidobacterium dentium, Paraprevotella clara YIT 11840, Enterococcus sp. 45, Bacteroides sp. 45, Bacillus sp. 46, Escherichia sp. 33, Enterococcus casseliflavus, Bacteroides uniformis, Alistipes indistinctus YIT 12060, Bacteroides ovatus, Escherichia sp. 12, and Odoribacter laneus YIT 12061) and AD pathogenesis. In addition to this, we performed molecular docking to study the metabolite interactions in the AD drug targets. The ADME/T properties of these metabolites were also calculated and the results are discussed in detail.

Dendritic cell mineralocorticoid receptor controls blood pressure by regulating T helper 17 differentiation: role of the Plcβ1/4-Stat5-NF-κB pathway.

Dendritic cells (DCs) are closely related to blood pressure (BP) regulation. Mineralocorticoid receptor (MR) is an important drug target for antihypertensive treatment. However, the role of DC MR in the pathogenesis of hypertension has not been fully elucidated. This study aimed to determine the role of DC MR in BP regulation and to explore the mechanism. Renal biopsy and peripheral blood samples were collected from hypertensive patients (HTN) for immunostaining and flow cytometry. Dendritic cell MR knockout (DCMRKO) mice, DC MR overexpressing (DCMROV) mice, DCMROV/IL-17A knockout (DCMROV/IL-17AKO) mice and finerenone-treated C57BL/6 mice were infused with angiotensin II (Ang II) to establish hypertensive models. Western blotting, chromatin immunoprecipitation, co-immunoprecipitation, and in vivo DC depletion or adoptive transfer were used to delineate the functional importance of DC MR in hypertension development. Mineralocorticoid receptor antagonists (spironolactone and finerenone) suppressed DC aggregation and activation, as well as hypertension in HTN and mice. Compared with littermate control (LC) mice, dendritic cell MR knockout mice had strikingly decreased BPs and attenuated target organ damage after Ang II infusion. Flow cytometry showed that DC MR deficiency mitigated Ang II-induced DC activation and T helper 17 (Th17) cell differentiation. RNA sequencing revealed that MR-deficient DCs had elevated expression of Plcβ1 and Plcβ4, knockdown of which reversed the inhibitory effect of MR deficiency on DC activation and Th17 differentiation. Adoptive transfer of MR-deficient DCs protected Ang II-induced hypertension, whereas knockdown of Plcβ1/4 eliminated the protective effects. At the molecular level, MR negatively regulated Plcβ1/4, which recruited SHP-1 to inactivate of Stat5 activity, resulting in enhanced NF-κB activation and Th17 polarization. Furthermore, DCMROV mice manifested more elevated BPs and target organ damage than control mice after Ang II infusion, and these differences were abolished in DCMROV/IL-17AKO mice. Finally, MR antagonists decreased the aggregation of Th17 in HTN and mice. Dendritic cell MR plays important roles in the pathogenesis of hypertension by regulating Th17 through Plcβ1/4-Stat5-NF-κB signalling, and blockade of DC MR is beneficial for treating hypertension.

Structure–Tissue Exposure/Selectivity Relationship (STR) on Carbamates of Cannabidiol

The structure–tissue exposure/selectivity relationship (STR) aids in lead optimization to improve drug candidate selection and balance clinical dose, efficacy, and toxicity. In this work, butyrocholinesterase (BuChE)-targeted cannabidiol (CBD) carbamates were used to study the STR in correlation with observed efficacy/toxicity. CBD carbamates with similar structures and same molecular target showed similar/different pharmacokinetics. L2 and L4 had almost same plasma exposure, which was not correlated with their exposure in the brain, while tissue exposure/selectivity was correlated with efficacy/safety. Structural modifications of CBD carbamates not only changed drug plasma exposure, but also altered drug tissue exposure/selectivity. The secondary amine of carbamate can be metabolized into CBD, while the tertiary amine is more stable. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters can be used to predict STR. Therefore, STR can alter drug tissue exposure/selectivity in normal tissues, impacting efficacy/toxicity. The drug optimization process should balance the structure–activity relationship (SAR) and STR of drug candidates for improving clinical trials.

Integrative analysis of transcriptome and proteome wide association studies prioritized functional genes for obesity.

Genome-wide association studies have identified dozens of genomic loci for obesity. However, functional genes and their detailed genetic mechanisms underlying these loci are mainly unknown. In this study, we conducted an integrative study to prioritize plausibly functional genes by combining information from genome-, transcriptome- and proteome-wide association analyses. We first conducted proteome-wide association analyses and transcriptome-wide association analyses for the six obesity-related traits. We then performed colocalization analysis on the identified loci shared between the proteome- and transcriptome-association analyses. Finally, we validated the identified genes with other plasma/blood reference panels. The highlighted genes were assessed for expression of other tissues, single-cell and tissue specificity, and druggability. We prioritized 4 high-confidence genes (FASN, ICAM1, PDCD6IP, and YWHAB) by proteome-wide association studies, transcriptome-wide association studies, and colocalization analyses, which consistently influenced the variation of obesity traits at both mRNA and protein levels. These 4 genes were successfully validated using other plasma/blood reference panels. These 4 genes shared regulatory structures in obesity-related tissues. Single-cell and tissue-specific analyses showed that FASN and ICAM1 were explicitly expressed in metabolism- and immunity-related tissues and cells. Furthermore, FASN and ICAM1 had been developed as drug targets. Our study provided novel promising protein targets for further mechanistic and therapeutic studies of obesity.

Alterations in store-operated calcium entry in neurodegenerative pathologies: history, facts, perspectives

Neurodegenerative disorders, along with cardiovascular and oncological pathologies, are one of the most actual issues facing modern medicine. Therefore, the study of the molecular mechanisms of their pathogenesis and the search for new drug targets is highly demanded. Neuronal calcium signalling has attracted close attention, as altered calcium homeostasis has been demonstrated in the pathogenesis of various neurodegenerative diseases. In this review, we focus on one of the most ubiquitous and important pathways for calcium uptake: store-operated calcium entry. Here we describe studies demonstrating disturbances in store-operated calcium entry in various neurodegenerative pathologies, including Alzheimer’s, Parkinson’s and Huntington’s diseases. Also, we analyse the molecular determinants underlying these disturbances and propose ways for pharmacological correction of altered calcium signaling. The information summarized in the review will allow us to consider store-operated calcium channels as promising targets for the drug development in order to treat neurodegenerative pathologies and outline further promising directions for the investigation.

Combatting melioidosis with chemical synthetic lethality

Burkholderia thailandensis has emerged as a nonpathogenic surrogate for Burkholderia pseudomallei, the causative agent of melioidosis, and an important Gram-negative model bacterium for studying the biosynthesis and regulation of secondary metabolism. We recently reported that subinhibitory concentrations of trimethoprim induce vast changes in both the primary and secondary metabolome of B. thailandensis. In the current work, we show that the folate biosynthetic enzyme FolE2 is permissive under standard growth conditions but essential for B. thailandensis in the presence of subinhibitory doses of trimethoprim. Reasoning that FolE2 may serve as an attractive drug target, we screened for and identified ten inhibitors, including dehydrocostus lactone (DHL), parthenolide, and β-lapachone, all of which are innocuous individually but form a chemical-synthetic lethal combination with subinhibitory doses of trimethoprim. We show that DHL is a mechanism-based inhibitor of FolE2 and capture the structure of the covalently inhibited enzyme using X-ray crystallography. In vitro, the combination of subinhibitory trimethoprim and DHL is more potent than Bactrim, the current standard of care against melioidosis. Moreover, unlike Bactrim, this combination does not affect the growth of most commensal and beneficial gut bacteria tested, thereby providing a degree of specificity against B. pseudomallei. Our work provides a path for identifying antimicrobial drug targets and for utilizing binary combinations of molecules that form a toxic cocktail based on metabolic idiosyncrasies of specific pathogens.

GPCR-BSD: a database of binding sites of human G-protein coupled receptors under diverse states

G-protein coupled receptors (GPCRs), the largest family of membrane proteins in human body, involve a great variety of biological processes and thus have become highly valuable drug targets. By binding with ligands (e.g., drugs), GPCRs switch between active and inactive conformational states, thereby performing functions such as signal transmission. The changes in binding pockets under different states are important for a better understanding of drug-target interactions. Therefore it is critical, as well as a practical need, to obtain binding sites in human GPCR structures. We report a database (called GPCR-BSD) that collects 127,990 predicted binding sites of 803 GPCRs under active and inactive states (thus 1,606 structures in total). The binding sites were identified from the predicted GPCR structures by executing three geometric-based pocket prediction methods, fpocket, CavityPlus and GHECOM. The server provides query, visualization, and comparison of the predicted binding sites for both GPCR predicted and experimentally determined structures recorded in PDB. We evaluated the identified pockets of 132 experimentally determined human GPCR structures in terms of pocket residue coverage, pocket center distance and redocking accuracy. The evaluation showed that fpocket and CavityPlus methods performed better and successfully predicted orthosteric binding sites in over 60% of the 132 experimentally determined structures. The GPCR Binding Site database is freely accessible at https://gpcrbs.bigdata.jcmsc.cn. This study not only provides a systematic evaluation of the commonly-used fpocket and CavityPlus methods for the first time but also meets the need for binding site information in GPCR studies.

Non-classical hormones from the fibroblast growth factor family

Fibroblast growth factors (FGFs) are a group of signaling molecules named for their ability to promote the growth and proliferation of fibroblasts and various other cell types. Typically, FGFs exert their effects locally by binding to receptors within the tissues where they are synthesized. However, certain members of this family, such as FGF 19, FGF 21, and FGF 23, diverge from this pattern. Following synthesis, these FGFs enter the bloodstream and act on distant organs and tissues by binding to their receptors and associated cofactors, thereby classified as non-classical hormones within the FGF family.The biological functions of FGFs are diverse and contingent upon the specific receptors and cofactors involved in their signaling pathways. For instance, FGF 19 and FGF 21 play crucial roles in regulating glucose and lipid metabolism, whereas FGF 23 primarily influences phosphorus metabolism. Given their varied roles, FGFs present promising targets for therapeutic interventions and drug development.This review aims to consolidate current understanding of FGF family hormones, elucidating their biological impacts and exploring their potential applications as therapeutic targets.

Understanding and Predicting Ligand Efficacy in the μ-Opioid Receptor through Quantitative Dynamical Analysis of Complex Structures.

The μ-opioid receptor (MOR) is a G-protein coupled receptor involved in nociception and the primary target of opioid drugs. Understanding the relationships among the ligand structure, receptor dynamics, and efficacy in activating MOR is crucial for drug discovery and development. Here, we use coarse-grained normal-mode analysis to predict ligand-induced changes in receptor dynamics with the Quantitative Dynamics Activity Relationship (QDAR) DynaSig-ML methodology, training a LASSO regression model on the entropic signatures (ESs) computed from ligand-receptor complexes. We train and validate the methodology using a data set of 179 MOR ligands with experimentally measured efficacies split into strictly chemically different cross-validation sets. By analyzing the coefficients of the ES LASSO model, we identified key residues involved in MOR activation, several of which have mutational data supporting their role in MOR activation. Additionally, we explored a contact-only LASSO model based on ligand-protein interactions. While the model showed predictive power, it failed at predicting efficacy for ligands with low structural similarity to the training set, emphasizing the importance of receptor dynamics for predicting ligand-induced receptor activation. Moreover, the low computational cost of our approach, at 3 CPU s per ligand-receptor complex, opens the door to its application in large-scale virtual screening contexts. Our work contributes to a better understanding of dynamics-function relationships in the μ-opioid receptor and provides a framework for predicting ligand efficacy based on ligand-induced changes in receptor dynamics.

Antivirulence therapy: type IV pilus as a druggable target for bacterial infections

Antivirulence therapy: type IV pilus as a druggable target for bacterial infections

Common molecular basis for MASH and hepatitis C revealed via systems biology approach

BackgroundMetabolic dysfunction-associated steatohepatitis (MASH) is characterized by liver inflammation and damage caused by a buildup of fat in the liver. Hepatitis C, caused by hepatitis C virus (HCV), is a disease that can lead to liver cirrhosis, liver cancer, and liver failure. MASH and hepatitis C are the common causes of liver cirrhosis and hepatocellular carcinoma. Several studies have shown that hepatic steatosis is also a common histological feature of liver in HCV infected patients. However, the common molecular basis for MASH and hepatitis C remains poorly understood.MethodsFirstly, differentially expressed genes (DEGs) for MASH and hepatitis C were extracted from the GSE89632, GSE164760 and GSE14323 datasets. Subsequently, the common DEGs shared among these datasets were determined using the Venn diagram. Next, a protein-protein interaction (PPI) network was constructed based on the common DEGs and the hub genes were extracted. Then, gene ontology (GO) and pathway analysis of the common DEGs were performed. Furthermore, transcription factors (TFs) and miRNAs regulatory networks were constructed, and drug candidates were identified. After the MASH and hepatitis C cell model was treated with predicted drug, the expression levels of the signature genes were measured by qRT-PCR and ELISA.Results866 common DEGs were identified in MASH and hepatitis C. The GO analysis showed that the most significantly enriched biological process of the DEGs was the positive regulation of cytokine production. 10 hub genes, including STAT1, CCL2, ITGAM, PTPRC, CXCL9, IL15, SELL, VCAM1, TLR4 and CCL5, were selected from the PPI network. By constructing the TF-gene and miRNA-gene network, most prominent TFs and miRNAs were screened out. Potential drugs screening shows that Budesonide and Dinoprostone may benefit patients, and cellular experiments showed that Budesonide effectively inhibited the expression of genes related to glycolipid metabolism, fibrosis, and inflammatory factors.ConclusionWe extracted 10 hub genes between MASH and hepatitis C, and performed a series of analyses on the genes. Molecular docking and in vitro studies have revealed that Budesonide can effectively suppress the progression of MASH and hepatitis C. This study can provide novel insights into the potential drug targets and biomarkers for MASH and hepatitis C.

Malignant Salivary Gland Neoplasm of the Tongue Base with EWSR1::BEND2 Fusion: An Unusual Case with Literature Review.

Salivary gland malignancies may have overlapping architectural patterns, tumor morphology, and immunohistochemical phenotypes, presenting challenges in precise classification. Molecular phenotyping has become quite useful for providing an additional diagnostic modality, and potential drug targets. Here we reported a young female patient with salivary gland tumor of the tongue base harboring genetic alterations by next generation sequencing (NGS). The morphological, immunohistochemical and molecular features of this case were described, and related literature was reviewed. The tumor showed an epithelial myoepithelial architecture arranged in cords and tubules interwoven with a chondromyxoid stroma, along with perineural invasion and adjacent striated muscle infiltration. Myoepithelial cells were positive for CK5/6, partially positive for P63 and CK7, and sporadically positive for S100. Immunoprofiling revealed a low density of infiltrating lymphocytes and macrophages and the absence of programmed death ligand 1 (PD-L1). Notably, RNA-based NGS showed EWSR1::BEND2 gene fusion in this tumor, and EWSR1 break-apart was confirmed by fluorescence in situ hybridization. This led to a final diagnosis of a minor salivary gland malignancy with EWSR1::BEND2 fusion. Only two other cases of salivary gland tumors with EWSR1::BEND2 fusion had been previously reported, which were also detected via RNA-based NGS. This study emphasized that EWSR1::BEND2 fusion may drive the carcinogenesis in salivary glands neoplasia. In clinic RNA-based NGS could be essential for precise genotyping of EWSR1 fusion in this rare disease.

Discovery of 18F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

The histamine subtype 3 (H3) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H3 receptor. In this study, we synthesized and evaluated the binding effects of [18F]H3-2404 and [18F]H3-2405 by modifying the structure of AZD5213, a selective H3 antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [18F]H3-2404 and [18F]H3-2405 are unsuitable as PET tracers for brain imaging of the H3 receptor, this study provides a valuable attempt for optimizing 18F labeled radiotracers based on AZD5213.

Research on the Therapeutic Effect of Qizhu Anti Cancer Recipe on Colorectal Cancer Based on RNA Sequencing Analysis.

Colorectal cancer is one of the common malignant tumors in clinical practice, and traditional Chinese medicine, as an important adjuvant treatment method, plays important roles in the treatment of malignant tumors. This study aims to explore the mechanism of action of the Qizhu anti-cancer recipe on colorectal cancer through transcriptome sequencing. The control group and Qizhu anti-cancer recipe group were established separately, and sequencing of the cells of the two groups was performed using the Illumina sequencing platform. Two sets of Differentially Expressed Genes (DEGs) were screened using the DESeq2 algorithm, and Principal Component Analysis (PCA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, Disease Ontology (DO), and Protein-Protein Interaction (PPI) were used to comprehensively analyze the molecular functions and signaling pathways enriched by DEGs. A total of 122 DEGs were identified through differential analysis, including 24 upregulated genes and 98 downregulated genes. GO analysis showed that DEGs were mainly enriched in functions such as alkaline phase activity, ion transport, cell differentiation, etc.; KEGG analysis showed that DEGs were mainly enriched in pathways such as Thiamine metabolism, apoptosis, signaling pathways regulating pluripotency of stem cells, cellular senescence and so on. Reactom analysis showed that DEGs were mainly enriched in response pathways such as EGR1,2,3 bind to the NAB2 promoter, EGR binds ARC gene, EGR-dependent NAB2 gene expression, etc.; DO analysis showed that differentially expressed genes were mainly enriched in diseases such as disease of cellular proliferation, disease of anatomical entity, organ system cancer, etc.; PPI analysis identified key differentially expressed genes, including DDIT3, CHAC1, TRIB3, and ASNS. Based on transcriptome sequencing and bioinformatics analysis, it was found that the Qizhu anti-cancer recipe may involve DEGs and signaling pathways in the treatment of colorectal cancer. Our study may provide potential drug targets for developing new treatment strategies for colorectal cancer.

Deferiprone in Alzheimer Disease

Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months. The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis). Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%). These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD. ClinicalTrials.gov Identifier: NCT03234686.

NFSA-DTI: A Novel Drug-Target Interaction Prediction Model Using Neural Fingerprint and Self-Attention Mechanism.

Existing deep learning methods have shown outstanding performance in predicting drug-target interactions. However, they still have limitations: (1) the over-reliance on locally extracted features by some single encoders, with insufficient consideration of global features, and (2) the inadequate modeling and learning of local crucial interaction sites in drug-target interaction pairs. In this study, we propose a novel drug-target interaction prediction model called the Neural Fingerprint and Self-Attention Mechanism (NFSA-DTI), which effectively integrates the local information of drug molecules and target sequences with their respective global features. The neural fingerprint method is used in this model to extract global features of drug molecules, while the self-attention mechanism is utilized to enhance CNN's capability in capturing the long-distance dependencies between the subsequences in the target amino acid sequence. In the feature fusion module, we improve the bilinear attention network by incorporating attention pooling, which enhances the model's ability to learn local crucial interaction sites in the drug-target pair. The experimental results on three benchmark datasets demonstrated that NFSA-DTI outperformed all baseline models in predictive performance. Furthermore, case studies illustrated that our model could provide valuable insights for drug discovery. Moreover, our model offers molecular-level interpretations.

Zymogen granule protein 16B (ZG16B) is a druggable epigenetic target to modulate the mammary extracellular matrix.

High tissue density of the mammary gland is considered a pro-tumorigenic factor, hence suppressing the stimuli that induce matrix buildup carries the potential for cancer interception. We found that in non-malignant mammary epithelial cells the combination of the chemopreventive agents bexarotene (Bex) and carvedilol (Carv) suppresses the zymogen granule protein 16B (ZG16B, PAUF) through an interaction of ARID1A with a proximal enhancer. Bex + Carv also reduced ZG16B levels invivo in normal breast tissue and MDA-MB231 tumor xenografts. The relevance of ZG16B is underscored by ongoing clinical trials targeting ZG16B in pancreatic cancers, but its role in breast cancer development is unclear. In immortalized mammary epithelial cells, secreted recombinant ZG16B stimulated mitogenic kinase phosphorylation, detachment and mesenchymal characteristics, and promoted proliferation, motility and clonogenic growth. Highly concerted induction of specific laminin, collagen and integrin isoforms indicated a shift in matrix properties toward increased density and cell-matrix interactions. Exogenous ZG16B alone blocked Bex + Carv-mediated control of cell growth and migration, and antagonized Bex + Carv-induced gene programs regulating cell adhesion and migration. In breast cancer cells ZG16B induced colony formation and anchorage-independent growth, and stimulated migration in a PI3K/Akt-dependent manner. In contrast, Bex + Carv inhibited colony formation, reduced Ki67 levels, ZG16B expression and glucose uptake in MDA-MB231 xenografts. These data establish ZG16B as a druggable pro-tumorigenic target in breast cell transformation and suggest a key role of the matrisome network in rexinoid-dependent antitumor activity.

Association between human blood metabolome and risk of myocarditis: a mendelian randomization study

Myocarditis is a common disease of the cardiovascular and immune systems, but the relationship between relevant blood metabolites and the risk of myocarditis has not been well-established. To identify potential biometabolic markers associated with myocarditis, we conducted a two-sample Mendelian randomization (MR) study. We performed preliminary MR analysis using the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode methods to adjust for false discovery rate (FDR). Confounders were screened using the GWAS Catalog website. Sensitivity analyses included Cochrane Q-test, Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), scatterplots, funnel plots, and forest plots. For genetic and directional analysis, we employed co-localization analysis and the Steiger test. MR analysis was performed using the FinnGen database and meta-analysis was performed using the IEU database. MR analysis identified significant correlations for five metabolic biomarkers after FDR correction. These included four known metabolites: kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, and 5-acetylamino-6-formylamino-3-methyluracil, as well as one unknown metabolite, X-25,422. Among these, kynurenine (OR = 1.441, 95%CI = 1.089–1.906, p-value = 0.018) and 1-stearoyl-GPE (18:0) (OR = 1.263, 95%CI = 1.029–1.550, p-value = 0.029) were identified as risk factors for myocarditis, while deoxycarnitine (OR = 0.813, 95%CI = 0.676–0.979, p-value = 0.029), 5-acetylamino-6-formylamino-3-methyluracil (OR = 0.864, 95% CI = 0.775–0.962, p-value = 0.018), and X-25,422 (OR = 0.721, 95%CI = 0.587–0.886, p-value = 0.009) were found to be protective factors. No evidence of heterogeneity, horizontal pleiotropy, or sensitivity issues was observed, and no shared genetic factors between exposure and outcome were detected. The causality was in the correct direction. Meta-analysis further confirmed the causal relationship between the five metabolites and myocarditis. This study identifies a causal relationship between five circulating metabolites and myocarditis. Kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, X-25,422, and 5-acetylamino-6-formylamino-3-methyluracil may serve as potential drug targets for myocarditis, providing a theoretical basis for the prevention, diagnosis, and treatment of the condition.