SEARCH · PubMed Health

Results for “molecular docking”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources

PubMed2025

Exploring potential targets and molecular mechanisms of traumatic brain injury exacerbated by Benzo(a)pyrene via network toxicology and molecular dynamics simulation.

Benzo(a)pyrene (BaP) is a common environmental pollutant from combustion sources that promotes oxidative stress, neuroinflammation and disruption of blood-brain barrier (BBB). However, its contribution to worsening traumatic brain injury (TBI) remains unclear. In this study, we aimed to assess the contribution of BaP to secondary injury in TBI. By integrating data from e.g., the Comparative Toxicogenomics Database, GeneCards, and Online Mendelian Inheritance in Man, 121 overlapping core targets were identified between BaP and TBI. Enrichment analyses via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, combined with protein-protein interaction networks and topological algorithms (degree, closeness centrality, betweenness centrality, average shortest path length, topological coefficient and partner of multi-edged node pairs), highlighted five hub genes (TP53, EGFR, AKT1, ACTB, and TNF) implicated in mitogen-activated protein kinase signaling, oxidative stress, and neuroinflammation. Molecular docking showed strong binding affinities of BaP to these hub proteins, with energies from -9.3 to -12.1 kcal/mol, tighter than co-crystal ligands and existing protein-binding drugs. Molecular dynamics simulations confirmed interaction stability through low root-mean-square deviation (< 0.5 nm), fluctuation, and radius of gyration values. Calculation of binding free energies using MM-PBSA validated the strong binding affinity between BaP and binding pockets of each hub genes. Toxicity prediction analysis revealed an oral LD50 of 316 mg/kg for BaP, with high probabilities for neurotoxicity, BBB permeability, carcinogenicity, and mutagenicity, associated with aryl hydrocarbon receptor activation. These findings reveal a "neurovascular homeostasis disruption" network underlying BaP-exacerbated TBI pathology and highlight potential targets to reduce pollution-related risks in TBI management.

Benzo(a)pyrene↗

PubMed2006

Synthesis, biological activity and molecular modelling of new trisubstituted 8-azaadenines with high affinity for A1 adenosine receptors.

We describe here the synthesis and biological activity of new 8-azaadenines bearing both a phenyl group on C(2) and a 9-benzyl group substituted in the ortho position with a Cl or a F atom or a CF(3) group, to verify the synergistic effect of a combination of these substitution patterns on binding with the A(1) adenosine receptors. In position N(6) aliphatic and cycloaliphatic substituents were chosen which had been shown to bind well with the A(1) receptors. Because of the high lipophilicity of these kinds of molecules, we also introduced a hydroxyalkyl substituent in the same position. The compounds obtained generally showed a very good affinity and selectivity for A(1) receptors. Some of the compounds showed K(i) in the nanomolar range, one even in the subnanomolar range (0.6 M). Molecular docking calculations were performed in order to evaluate the interaction energies between the bovine A(1) receptor model and the selected ligands, and then to correlate these energies with biological activities of the ligands as obtained from the experiments. Molecular docking analysis suggests different binding modes towards A(1) receptors that are plausible for these ligands.

Adenine↗

PubMed2006

Structural analysis of the protein phosphatase 1 docking motif: molecular description of binding specificities identifies interacting proteins.

The interplay between kinases and phosphatases represents a fundamental regulatory mechanism in biological systems. Being less numerous than kinases, phosphatases increase their diversity by the acquisition of a variety of binding partners, thereby forming a large number of holoenzymes. Proteins interacting with protein phosphatase 1 (PP1) often bind via a so-called docking motif to regulate its enzymatic activity, substrate specificity, and subcellular localization. Here, we systematically determined structural elements that mediate the binding specificity of PP1 interacting proteins, and propose a refined consensus sequence for high-affinity PP1 ligands. Applying this pattern to database searches, we predicted and experimentally confirmed several previously unknown PP1 interactors. Thus, the suggested PP1 docking motif enables a highly specific prediction of PP1 binding partners, thereby facilitating the genome-wide identification of PP1 interactors.

Amino Acid Motifs↗

PubMed2006

Computational studies of ligand-receptor interactions in bitter taste receptors.

Phenylthiocarbamide tastes intensely bitter to some individuals, but others find it completely tasteless. Recently, it was suggested that phenylthiocarbamide elicits bitter taste by interacting with a human G protein-coupled receptor (hTAS2R38) encoded by the PTC gene. The phenylthiocarbamide nontaster trait was linked to three single nucleotide polymorphisms occurring in the PTC gene. Using the crystal structure of bovine rhodopsin as template, we generated the 3D structure of hTAS2R38 bitter taste receptor. We were able to map on the receptor structure the amino acids affected by the genetic polymorphisms and to propose molecular functions for two of them that explained the emergence of the nontaster trait. We used molecular docking simulations to find that phenylthiocarbamide exhibited a higher affinity for the target receptor than the structurally similar molecule 6-n-propylthiouracil, in line with recent experimental studies. A 3D model was constructed for the hTAS2R16 bitter taste receptor as well, by applying the same protocol. We found that the recently published experimental ligand binding affinity data for this receptor correlated well with the binding scores obtained from our molecular docking calculations.

Animals↗

PubMed2004

Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition.

There has been much interest in the development of a predictive model of cytochrome P450 2D6 particularly because this enzyme is involved in the oxidation of at least 50 drugs. Previously we have described the combined use of homology modeling and molecular docking to correctly position a range of substrates in the CYP2D6 active site with the known sites of metabolism above the heme. Here, our approach identifies correctly the site of metabolism of the atypical (no basic nitrogen) cytochrome P450 2D6 substrate, spirosulfonamide. The same method is used to screen a small compound database for cytochrome P450 2D6 inhibition. A database containing 33 compounds from the National Cancer Institute database was docked into our cytochrome P450 2D6 homology model using the program GOLDv2.0. Experimental IC50 values for the 33 compounds were determined; comparison with the corresponding docked scores revealed a correlation with a regression coefficient of r2 = 0.61 (q2 = 0.59). The method was able to discriminate between tight and weak binding compounds and correctly identified several novel inhibitors. The results therefore suggest that our approach, which combines homology modeling with molecular docking, has produced a useful predictive in silico tool for cytochrome P450 2D6 inhibition, which is best used as one filter in a multifilter database screen.

Binding Sites↗

PubMed2005

Virtual screening of biogenic amine-binding G-protein coupled receptors: comparative evaluation of protein- and ligand-based virtual screening protocols.

In this paper, we compare protein- and ligand-based virtual screening techniques for identifying the ligands of four biogenic amine-binding G-protein coupled receptors (GPCRs). For the screening of the virtual compound libraries, we used (1) molecular docking into GPCR homology models, (2) ligand-based pharmacophore and Feature Tree models, (3) three-dimensional (3D)-similarity searches, and (4) statistical methods [partial least squares (PLS) and partial least squares discriminant analysis (PLS-DA) models] based on two-dimensional (2D) molecular descriptors. The comparison of the different methods in retrieving known antagonists from virtual libraries shows that in our study the ligand-based pharmacophore-, Feature Tree-, and 2D quantitative structure-activity relationship (QSAR)-based screening techniques provide enrichment factors that are higher than those provided by molecular docking into the GPCR homology models. Nevertheless, the hit rates achieved when docking with GOLD and ranking the ligands with GoldScore (up to 60% among the top-ranked 1% of the screened databases) are still satisfying. These results suggest that docking into GPCR homology models can be a useful approach for lead finding by virtual screening when either little or no information about the active ligands is available.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2026

Prenatal BPA exposure perturbs RNA-binding protein-mediated splicing regulation and synaptogenesis in the developing cerebellum in a sex-dependent manner.

BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social communication deficits, exhibiting a male bias in prevalence. Emerging evidence suggests that prenatal exposure to bisphenol A (BPA) may perturb neurodevelopmental trajectories relevant to ASD. While the cerebellum is increasingly recognized as a brain region implicated in ASD pathophysiology, the impact of gestational BPA exposure on its post-transcriptional alternative splicing machinery remains fundamentally undefined. METHODS: Here, we investigated sex-dependent effects of prenatal BPA exposure on the alternative splicing landscape of the neonatal rat cerebellum. We utilized RNA-seq to profile differential alternative splicing (DAS) events. Ingenuity Pathway Analysis (IPA) was used to predict biological functions and canonical pathways, and to construct the interactome network of DAS genes. To explore candidate upstream regulatory mechanisms, we performed in silico molecular docking and used high-resolution melting (HRM) qRT-PCR to validate selected splicing events. Furthermore, we assessed in vitro cellular phenotypes in primary cerebellar neurons by measuring MTS-based viability and Syn1/Psd95 puncta colocalization. RESULTS: Prenatal BPA exposure was associated with widespread DAS in genes enriched for ASD-relevant pathways in the neonatal rat cerebellum. To our knowledge, this study is the first to report molecular docking analyses predicting favorable interactions between BPA and several candidate RNA-binding proteins (RBPs), including CPEB1, RALYL, HNRNPDL, and ACO1. Our findings support a model in which BPA may perturb RBP-associated splicing regulation, including altered splicing of chromatin regulators such as Ccar1 in males. These molecular and cellular findings were accompanied by sex-stratified differences in neuronal viability and synaptic puncta measurements. BPA exposure was associated with an increased MTS viability signal in male primary cerebellar neurons, together with significant reductions in Psd95 and Syn1 puncta density, whereas female neurons showed significantly increased synaptic puncta colocalization together with reduced viability. CONCLUSIONS: In this study, we propose that prenatal BPA may be relevant to ASD-related neurodevelopmental pathways through sex-dependent changes in RBP-associated alternative splicing, including altered splicing of Ccar1 in males, together with distinct cellular outcomes. Together, these findings identify the developing cerebellum as a sensitive target of prenatal BPA exposure and highlight alternative splicing as a candidate pathway relevant to ASD biology.

Animals↗

PubMed2005

A pharmacophore-based evolutionary approach for screening selective estrogen receptor modulators.

We developed a pharmacophore-based evolutionary approach for virtual screening. This tool, termed the Generic Evolutionary Method for molecular DOCKing (GEMDOCK), combines an evolutionary approach with a new pharmacophore-based scoring function. The former integrates discrete and continuous global search strategies with local search strategies to expedite convergence. The latter, integrating an empirical-based energy function and pharmacological preferences (binding-site pharmacological interactions and ligand preferences), simultaneously serves as the scoring function for both molecular docking and postdocking analyses to improve screening accuracy. We apply pharmacological interaction preferences to select the ligands that form pharmacological interactions with target proteins, and use the ligand preferences to eliminate the ligands that violate the electrostatic or hydrophilic constraints. We assessed the accuracy of our approach using human estrogen receptor (ER) and a ligand database from the comparative studies of Bissantz et al. (J Med Chem 2000;43:4759-4767). Using GEMDOCK, the average goodness-of-hit (GH) score was 0.83 and the average false-positive rate was 0.13% for ER antagonists, and the average GH score was 0.48 and the average false-positive rate was 0.75% for ER agonists. The performance of GEMDOCK was superior to competing methods such as GOLD and DOCK. We found that our pharmacophore-based scoring function indeed was able to reduce the number of false positives; moreover, the resulting pharmacological interactions at the binding site, as well as ligand preferences, were important to the screening accuracy of our experiments. These results suggest that GEMDOCK constitutes a robust tool for virtual database screening.

Binding Sites↗

PubMed2026

In silico identification of DNMT1 inhibitors from the PlantCyc database through computational approach to assess the anti-cancer potential of nutraceutical compounds in breast cancer.

Breast cancer accounts for a disproportionate share of global cancer-related deaths, with 670,000 fatalities and 2.3 million new diagnoses recorded in women during 2022 alone. Existing treatment modalities carry considerable toxicity burdens, and resistance to available agents remains an unresolved clinical problem. DNA methyltransferase 1 (DNMT1), the enzyme chiefly responsible for maintaining genome-wide methylation patterns during DNA replication, has been mapped out as a high-value target in breast cancer because its dysregulation silences tumour suppressor genes through promoter hypermethylation. The present work involves hierarchical in silico workflow to screen 4549 plant-derived compounds from the PlantCyc database (v16.0.3) against the human DNMT1 catalytic domain (PDB ID: 4WXX). Ten top-scoring compounds were taken forward for molecular docking via AutoDock Vina; Quercetin and Kaempferol both recorded the highest binding affinities at -9.5 kcal/mol, Wogonin (-9.3 kcal/mol) and Xanthohumol (-8.1 kcal/mol) also emerged as strong binders. Pharmacokinetic evaluation using ADMET-AI confirmed that all 10 compounds met Lipinski's rule of five, with human intestinal absorption values at or above 0.98. Wogonin and Xanthohumol were selected for a 100 ns all-atom molecular dynamics (MD) simulation in GROMACS due to their well-rounded ADMET profiles and limited existing data on their specific interactions with DNMT1 in breast cancer. Across all measured trajectory metrics, backbone RMSD, residue fluctuation, radius of gyration, solvent-accessible surface area, and intermolecular hydrogen bond count, Wogonin formed a more stable, compact complex. These findings suggest that Wogonin and Xanthohumol are non-toxic nutraceutical candidates suitable for DNMT1 targeted epigenetic therapy, with computational foundation strong enough to facilitate future in vitro and in vivo validation work.

Humans↗

PubMed2003

The quaternary structure of the Saccharomyces cerevisiae succinate dehydrogenase. Homology modeling, cofactor docking, and molecular dynamics simulation studies.

Succinate dehydrogenases and fumarate reductases are complex mitochondrial or bacterial respiratory chain proteins with remarkably similar structures and functions. Succinate dehydrogenase oxidizes succinate and reduces ubiquinone using a flavin adenine dinucleotide cofactor and iron-sulfur clusters to transport electrons. A model of the quaternary structure of the tetrameric Saccharomyces cerevisiae succinate dehydrogenase was constructed based on the crystal structures of the Escherichia coli succinate dehydrogenase, the E. coli fumarate reductase, and the Wolinella succinogenes fumarate reductase. One FAD and three iron-sulfur clusters were docked into the Sdh1p and Sdh2p catalytic dimer. One b-type heme and two ubiquinone or inhibitor analog molecules were docked into the Sdh3p and Sdh4p membrane dimer. The model is consistent with numerous experimental observations. The calculated free energies of inhibitor binding are in excellent agreement with the experimentally determined inhibitory constants. Functionally important residues identified by mutagenesis of the SDH3 and SDH4 genes are located near the two proposed quinone-binding sites, which are separated by the heme. The proximal quinone-binding site, located nearest the catalytic dimer, has a considerably more polar environment than the distal site. Alternative low energy conformations of the membrane subunits were explored in a molecular dynamics simulation of the dimer embedded in a phospholipid bilayer. The simulation offers insight into why Sdh4p Cys-78 may be serving as the second axial ligand for the heme instead of a histidine residue. We discuss the possible roles of heme and of the two quinone-binding sites in electron transport.

Amino Acid Sequence↗

PubMed2026

Direct targeting of ORAI1 by ginsenoside Rg3 modulates calcium signaling and senescence-associated AMPK-NRF2 activation.

BACKGROUND: 20(S)-ginsenoside Rg3 (Rg3(S)), a major saponin derived from red ginseng, exhibits diverse biological activities, including antioxidant and anti-senescence effects. However, the direct molecular targets through which Rg3(S) regulates calcium signaling and its role at membrane contact sites during cellular senescence remain largely unknown. METHODS: Plasma membrane (PM)-endoplasmic reticulum (ER) contacts and related protein interactions were analyzed using proximity ligation assays and co-immunoprecipitation. Direct binding of Rg3(S) to ORAI1 was validated using cellular thermal shift assays and microscale thermophoresis. Molecular docking simulations followed by site-directed mutagenesis were used to define critical binding residues. Cytosolic calcium levels and cellular senescence were assessed using calcium imaging and senescence-associated β-galactosidase staining. RESULTS: Rg3(S) increased cytosolic calcium levels independently of ER calcium depletion and was accompanied by a reduction in PM-ER contacts. Rg3(S) directly bound to ORAI1 in a dose-dependent manner, identifying ORAI1 as a previously unrecognized molecular target of ginsenoside Rg3. Molecular docking revealed LYS204 and ILE229 within the extracellular loop of ORAI1 as key residues maintaining this interaction. Mutation of these residues abolished Rg3(S)-induced calcium influx, leading to impaired activation of the AMPK-NRF2 pathway and attenuation of the anti-senescence effect of Rg3(S). CONCLUSION: These findings identify ORAI1 as a key molecular mediator of ginsenoside Rg3(S)-induced calcium signaling linked to cellular senescence. By modulating PM-ER contact sites and cytosolic calcium dynamics, Rg3(S) attenuates senescence, providing new mechanistic insight into the anti-aging potential of ginseng-derived compounds beyond autophagy-centered pathways.

Calcium signaling↗

PubMed2026

Study on the mechanism of SW inhibiting testosterone synthesis in mouse Leydig cells.

BACKGROUND: Swainsonine (SW), the main toxic component of locoweed, can cause livestock poisoning and reproductive damage in male animals; however, the mechanism by which it affects testosterone secretion remains unclear. METHODS: Ten-week-old male C57BL/6 mice were orally administered SW at doses of 0, 0.05, and 0.25 mg/(kg·d) for 28 days. TM3 mouse Leydig cells were treated with SW at concentrations of 0, 1, and 10 nM for 24 h. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed on RNA-seq data from mouse testicular tissues to identify differentially enriched pathways between the control and SW-treated groups. Testosterone secretion levels were measured using an enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of steroidogenesis-related genes (StAR, Cyp11a1, Hsd3b2, and Hsd17b3) were detected by qPCR, while the expression of the steroidogenic acute regulatory (STAR) protein was detected by western blotting. AutoDock Vina molecular docking was used to predict the binding affinity between SW and the STAR protein. RESULTS: KEGG analysis revealed a significant enrichment of pathways related to steroid synthesis. In both the mouse model and TM3 cells, SW significantly inhibited testosterone secretion, downregulated the mRNA expression of StAR, Cyp11a1, Hsd3b2, and Hsd17b3, and reduced the protein expression of STAR. Molecular docking analysis revealed multiple potential hydrogen-bond interaction sites between SW and STAR. CONCLUSION: SW downregulates the expression of steroidogenesis-related genes and STAR protein, thereby suppressing testosterone secretion in male mice and TM3 cells.

Swainsonine↗

PubMed2004

Virtual screening in lead discovery and optimization.

Virtual screening by molecular docking, using a protein with an experimentally determined structure as a target, has become an established method for lead discovery and for enhancing efficiency in lead optimization. Generalizations of the quantitative structure-activity relationship concept have led to approaches for virtual screening in the absence of a protein target structure, instead relying upon ligand-based models as surrogates of protein active sites. Recently reported methods for ligand-based virtual screening can achieve similar enrichment rates to those obtained using molecular docking. This review will discuss recent advances in both domains of virtual screening, including theoretical and practical advances and the implications for their application.

Computational Biology↗

PubMed2026

Integrative Network Analysis of Bioactive Compounds from Punica granatum L. Peel: Multi-Target Mechanisms in Wound Healing.

BACKGROUND: Wound-healing agents often have limited efficacy and require prolonged recovery times, prompting growing interest in developing herbal-based formulations. Among these, Punica granatum L. has attracted considerable attention because of its high polyphenolic content. Despite its widespread use, the precise pharmacological targets underlying its wound-healing effects remain poorly understood and require systematic investigation. OBJECTIVES: This study aimed to elucidate the underlying pharmacological mechanisms of the topical wound-healing properties of P. granatum L. using a network pharmacology approach. METHODS: Bioactive compounds of P. granatum L. and their potential target genes were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Similarity Ensemble Approach (SEA), and SwissTargetPrediction databases. Wound healing-related genes were retrieved from the GeneCards database. Genes intersecting P. granatum L. targets and wound healing-associated genes were subjected to functional enrichment analyses, including protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The PPI network was further analyzed using Cytoscape, and the phytoconstituent-target interaction network was visualized using Gephi. These findings were validated using molecular docking. RESULTS: A total of 40 intersecting genes were identified as potential P. granatum L. targets involved in wound healing. Among these, EGFR, PTPN11, HRAS, IGF1R, and ESR1 were identified as key hub genes. Functional enrichment analysis indicated that the most significantly enriched signaling pathways included the MAPK, PI3K-Akt, EGFR tyrosine kinase inhibitor resistance, focal adhesion, and FoxO signaling pathways. Molecular docking analysis confirmed favorable binding of quercetin and ellagic acid to the hub targets EGFR, IGF1R, and ESR1. CONCLUSIONS: These findings elucidate the pharmacological pathways underlying P. granatum-mediated wound healing and suggest that P. granatum L. acts as a multi-target modulator in the wound-healing process.

Focal Adhesion↗

PubMed2026

Investigating the mechanisms of PhIP-induced colorectal cancer through network toxicology, machine learning, and molecular dynamics simulation.

BACKGROUND: Over the past few years, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)- a compound from grilled or processed meats-has emerged as a major player in cancer development, especially colorectal cancer (CRC). This work dives into its potential links to CRC and uncovers the key genes that bridge this connection. METHODS: We tapped into various databases to pinpoint target genes tied to PhIP and CRC, then ran protein-protein interaction (PPI) analyses for visualization. Next, we explored underlying mechanisms through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. To nail down predictions, we tested 107 machine learning pipelines and picked the best one, validating its accuracy and the core genes' prognostic value across datasets. Next, molecular docking and dynamics simulations probed the interactions between these genes and PhIP. Finally, cell proliferation was assessed using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, and polymerase chain reaction (PCR) was performed to validate the expression levels of the hub genes. RESULTS: Our analysis identified 39 overlapping genes, from which a machine learning model (glmBoost + Enet) identified six candidate targets: CDK4, CEBPB, COMT, SOX9, TIMP1, and TOP2A. To prioritize these, a hierarchical screening framework was applied. Molecular docking and dynamics simulations identified CDK4, COMT, and TIMP1 as the most stable interactors with PhIP. Functional assays confirmed that PhIP treatment significantly enhanced the proliferation of CRC cells. Crucially, quantitative PCR (qPCR) validation in multiple CRC cell lines identified TIMP1 as the primary target, showing the most consistent and significant upregulation upon PhIP exposure. CONCLUSIONS: In essence, these genes drive PhIP is role in CRC, offering novel insights into its molecular pathways. This could reshape how we tackle food-related pollutants, paving the way for better prevention and targeted therapies.

Colorectal cancer (CRC)↗

PubMed2026

Genomic exploration and in silico prioritization of putative COX-2-targeting metabolites from Streptomyces sp. VITGV156 (MCC 4965).

INTRODUCTION: Streptomyces species represent an important source of bioactive natural products, yet systematic genome-guided prioritization of metabolites targeting cyclooxygenase-2 (COX-2/PTGS2) remains limited. This study aimed to investigate the biosynthetic potential of Streptomyces sp. VITGV156 (MCC 4965) using an integrated genome mining and computational drug discovery pipeline. METHODS: Whole-genome sequencing, functional annotation, antiSMASH v7.0.1-based biosynthetic gene cluster (BGC) prediction, LC-MS/MS metabolomic profiling, SwissADME analysis, target prediction, disease association mapping, molecular docking against PTGS2 (PDB: 5IKR), and PASS bioactivity prediction were performed to prioritize putative bioactive metabolites. RESULTS: Genome analysis identified 29 predicted biosynthetic gene clusters, including clusters associated with geosmin, ectoine, albaflavenone, hopene, coelichelin, and SapB, together with several cryptic clusters exhibiting low similarity to known pathways. LC-MS/MS metabolomic profiling provided experimental support for active secondary metabolite production under the cultivation conditions employed. Computational prioritization identified PTGS2 (COX-2) as a biologically relevant target. Molecular docking demonstrated favorable binding affinities and interaction profiles for several predicted metabolites within the PTGS2 catalytic pocket. PASS analysis further suggested potential anticancer-related biological activities that require experimental validation. DISCUSSION: These findings demonstrate the utility of integrating genome mining, metabolomic profiling, and computational drug discovery for prioritizing natural-product candidates. Streptomyces sp. VITGV156 (MCC 4965) represents a promising source of biosynthetic diversity and provides a genome-guided framework for identifying putative COX-2-targeting natural products for future experimental validation rather than confirming metabolite production or biological activity.

COX-2 (PTGS2)↗

PubMed2026

Multiomics approaches reveal direct NF-κB p65 target genes in pancreatic islets during cytokine exposure and in type 1 diabetes.

Autoimmune diseases, including Type 1 diabetes (T1D), are often characterized by overactive inflammatory signaling pathways. The proinflammatory cytokine interleukin-1β (IL-1β) elicits global gene expression changes in islet β-cells which overlap with islets obtained from human donors with T1D. The direct transcriptional link between NF-κB subunit p65 and target genes involved with autoimmune events was investigated. We used a multiomics approach including bulk RNA-sequencing (RNA-Seq), single-cell RNA-sequencing (scRNA-Seq), and chromatin immunoprecipitation coupled to deep sequencing (ChIP-Seq), alongside molecular docking simulations, and transcriptional assays. Through the various experimental modalities, we identified early response genes driven by IL-1β that were differentially expressed in pancreatic islets from human T1D donors and also conserved across mouse, rat, and human tissues. ChIP-Seq revealed genes that are direct genomic targets of the NF-κB p65 transcription factor. Moreover, regions that gained RNA polymerase II binding following cellular exposure to IL-1β were identified, complementing the early response gene profile induced by β-cell exposure to IL-1β. Molecular docking simulations predicted that mutations reducing p65 transcriptional capacity do not alter DNA binding ability. These findings clearly show that IL-1β signaling in pancreatic β-cells directs p65 to specific genomic regions congruent with increased gene expression relevant to T1D in β-cell lines as well as mouse and human islets exposed to cytokines. Islets from human donors with T1D express genes identified as direct p65 targets using unbiased approaches, implicating heightened NF-κB activity as a critical component of autoimmune disease etiology.NEW & NOTEWORTHY Using multiple Seq-based approaches, this study identified genes expressed in human pancreatic tissue from donors with Type 1 diabetes that are regulated acutely by exposure to the cytokine interleukin-1beta. The NF-kB transcription factor p65 (RelA) was determined via ChIP-Seq to be a major control node regulating this immediate early response. These collective datasets are consistent with a paradigm of overactive NF-kB signaling as a critical component of autoimmunity in both rodents and humans.

Humans↗

PubMed2004

Binding analyses between Human PPARgamma-LBD and ligands.

The binding characteristics of a series of PPARgamma ligands (GW9662, GI 262570, cis-parinaric acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), LY171883, indomethacin, linoleic acid, palmitic acid and troglitazone) to human PPARgamma ligand binding domain have been investigated for the first time by using surface plasmon resonance biosensor technology, CD spectroscopy and molecular docking simulation. The surface plasmon resonance biosensor determined equilibrium dissociation constants (KD values) are in agreement with the results reported in the literature measured by other methods, indicating that the surface plasmon resonance biosensor can assume a direct assay method in screening new PPARgamma agonists or antagonists. Conformational changes of PPARgamma caused by the ligand binding were detected by CD determination. It is interesting that the thermal stability of the receptor, reflected by the increase of the transition temperature (T(m)), was enhanced by the binding of the ligands. The increment of the transition temperature (DeltaT(m)) of PPARgamma owing to ligand binding correlated well with the binding affinity. This finding implies that CD could possibly be a complementary technology with which to determine the binding affinities of ligands to PPARgamma. Molecular docking simulation provided reasonable and reliable binding models of the ligands to PPARgamma at the atomic level, which gave a good explanation of the structure-binding affinity relationship for the ligands interacting with PPARgamma. Moreover, the predicted binding free energies for the ligands correlated well with the binding constants measured by the surface plasmon resonance biosensor, indicating that the docking paradigm used in this study could possibly be employed in virtual screening to discover new PPARgamma ligands, although the docking program cannot accurately predict the absolute ligand-PPARgamma binding affinity.

Apoproteins↗