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Results for “molecular docking”

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PubMed2005

PatchDock and SymmDock: servers for rigid and symmetric docking.

Here, we describe two freely available web servers for molecular docking. The PatchDock method performs structure prediction of protein-protein and protein-small molecule complexes. The SymmDock method predicts the structure of a homomultimer with cyclic symmetry given the structure of the monomeric unit. The inputs to the servers are either protein PDB codes or uploaded protein structures. The services are available at http://bioinfo3d.cs.tau.ac.il. The methods behind the servers are very efficient, allowing large-scale docking experiments.

Algorithms↗

PubMed1997

Mean field analysis of FKBP12 complexes with FK506 and rapamycin: implications for a role of crystallographic water molecules in molecular recognition and specificity.

Mean field analysis of FKBP12 complexes with FK506 and rapamycin has been performed by using structures obtained from molecular docking simulations on a simple, yet robust molecular recognition energy landscape. When crystallographic water molecules are included in the simulations as an extension of the FKBP12 protein surface, there is an appreciable stability gap between the energy of the native FKBP12-FK506 complex and energies of conformations with the "native-like" binding mode. By contrast, the energy spectrum of the FKBP12-rapamycin complex is dense regardless of the presence of the water molecules. The stability gap in the FKBP12-FK506 system is determined by two critical water molecules from the effector region that participate in a network of specific hydrogen bond interactions. This interaction pattern protects the integrity and precision of the composite ligand-protein effector surface in the binary FKBP12-FK506 complex and is preserved in the crystal structure of the FKBP12-FK506-calcineurin ternary complex. These features of the binding energy landscapes provide useful insights into specific and nonspecific aspects of FK506 and rapamycin recognition.

Carrier Proteins↗

PubMed1996

The binding mode of an E-64 analog to the active site of cathepsin B.

Two binding modes of the isobutyl-NH-Eps-Leu-Pro inhibitor to cathepsin B have been proposed. Molecular docking using an empirical force field was carried out to distinguish between the two modes. The search began with manual docking, followed by random perturbations of the docking conformation and cycles of Monte Carlo minimization. Finally, molecular dynamics was carried out for the most favorable docking conformations. The present calculations predict that the isobutyl-NH-Eps-Leu-Pro inhibitor preferentially binds to the S' rather than the S subsites of cathepsin B. The S' binding mode prediction is supported by the X-ray crystal structure of cathepsin B bound to a closely related ethyl-O-Eps-Ile-Pro inhibitor, which was found to bind in the S'subsite with the C-terminal epoxy ring carbon making a covalent bond to the sulfur atom of Cys29. This agreement, in turn, validates our docking strategy. Furthermore, the calculations provide evidence that the dominant contribution to the total stabilization energy of the enzyme-inhibitor complex stems from the strong electrostatic interaction between the negatively charged C-terminal carboxylate group of the ligand and the positively charged imidazolium rings of His110 and His111. The latter are stabilized and held in an optimal orientation for interactions with the C-terminal end of the ligand through a salt bridge between the side chains of His110 and Asp22. By comparison with the crystal structure, some insight into the specificity of the epoxyldipeptide family towards cathepsin B inhibition has been extracted. Both the characteristics of the enzyme (e.g. subsite size and hydrophobicity) as well as the nature of the inhibitor influence the selectivity of an inhibitor towards an enzyme.

Binding Sites↗

PubMed2026

Integrated Genome Mining and Bioactivity-Guided Isolation of Antimicrobial Peptides from Bacillus amyloliquefaciens BS4.

Bacterial resistance remains a critical global health challenge, driving the continuous search for novel antimicrobial agents. Bacillus amyloliquefaciens is a recognized repository of bioactive metabolites; however, its full biosynthetic potential requires integrated genomic and experimental validation. This study characterized the antimicrobial profile of B. amyloliquefaciens BS4 through a hybrid pipeline. Genome sequencing and de novo assembly revealed a 3.9 Mb chromosome with a G + C content of 46.14%. Functional annotation identified 3,887 coding sequences, including pathways for siderophore biosynthesis and a complete bacilysin biosynthetic cluster. BGC analysis using antiSMASH v7.1.0 and BAGEL4 identified 18 biosynthetic gene clusters, while similarity network analysis via BiG-SCAPE highlighted unique singleton BGCs, indicating untapped biosynthetic diversity. Although in silico screening via Macrel predicted two putative cationic antimicrobial peptides (AMPs), bioactivity-guided purification utilizing sequential RP-HPLC, and de novo sequencing revealed a distinct set of four active peptides. Notably, three of these sequences were identified as fragments derived from the BclA exosporium protein family, highlighting the structural proteome as a non-canonical source of antimicrobials. The purified fractions exhibited activity against M. luteus and E. coli, while displaying no significant hemolytic activity or cytotoxicity, even above the MIC values. Molecular docking further supported the interaction of these candidates with bacterial targets. Overall, this hybrid strategy effectively uncovers the antimicrobial complexity of BS4, revealing 'cryptic' peptide candidates with therapeutic potential.

Bacillus amyloliquefaciens BS4↗

PubMed2024

An integrated in-silico approach for drug target identification in human pathogen Shigella dysenteriae.

Shigella dysenteriae, is a Gram-negative bacterium that emerged as the second most significant cause of bacillary dysentery. Antibiotic treatment is vital in lowering Shigella infection rates, yet the growing global resistance to broad-spectrum antibiotics poses a significant challenge. The persistent multidrug resistance of S. dysenteriae complicates its management and control. Hence, there is an urgent requirement to discover novel therapeutic targets and potent medications to prevent and treat this disease. Therefore, the integration of bioinformatics methods such as subtractive and comparative analysis provides a pathway to compute the pan-genome of S. dysenteriae. In our study, we analysed a dataset comprising 27 whole genomes. The S. dysenteriae strain SD197 was used as the reference for determining the core genome. Initially, our focus was directed towards the identification of the proteome of the core genome. Moreover, several filters were applied to the core genome, including assessments for non-host homology, protein essentiality, and virulence, in order to prioritize potential drug targets. Among these targets were Integration host factor subunit alpha and Tyrosine recombinase XerC. Furthermore, four drug-like compounds showing potential inhibitory effects against both target proteins were identified. Subsequently, molecular docking analysis was conducted involving these targets and the compounds. This initial study provides the list of novel targets against S. dysenteriae. Conclusively, future in vitro investigations could validate our in-silico findings and uncover potential therapeutic drugs for combating bacillary dysentery infection.

Shigella dysenteriae↗

PubMed2026

Highly Conserved Allelic Substitutions S202F, L244P, and H248P/R/Y in FsSdhB and A83 V in FsSdhC1 Trigger Gradual Resistance to Pydiflumetofen in Fusarium solani.

Pydiflumetofen (Pyd), one of the new-generation SDHIs, has been applied to control various diseases in economic crops. Fusarium solani, a soil-borne pathogen with a broad host range, is the agent of quinoa basal-stem rot (QBSR). In this study, three PydLR (4.64 < RF < 9.31), six PydMR (51.24 < RF < 86.91), and seven PydHR mutants (RF > 6000) were generated by Pyd-taming. Most F. solani PydR mutants showed no fitness penalties. The sequence alignment of FsSdh genes revealed that substitutions S202F, L244P, and H248P/R/Y in FsSdhB, or A83 V in FsSdhC1, caused Pyd resistance. Notably, the mutation S202F causing HR was first reported. Molecular docking demonstrated that these aforementioned mutations significantly reduced affinity between Pyd and the Qp-binding pocket. These results provide pivotal data for the resistance management strategies of F. solani and advance our understanding of the resistance mechanisms of SDHIs.

Fusarium↗

PubMed2025

Systematic understanding of mechanism of Shenfu decoction improve the prognosis of ischemic stroke using a network pharmacology and animal experiment approach.

OBJECTIVE: To explore the active compounds and the mechanism of Shenfu decoction (, SFD) against ischemic stroke (IS) through network pharmacology and animal experiments. METHODS: SFD components were retrieved from the Traditional Chinese Medicine (TCM) database. The Online Mendelian Inheritance in Man (OMIM), Comparative Toxicogenomics Database (CTD) and Therapeutic Target Database (TTD) database were used to retrieve the IS-related disease targets. The herb-compound-target network was built by Cytoscape 3.7.1 software. The core targets were obtained using protein-protein interaction (PPI) network. The core targets of SFD were further analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We then performed molecular docking between the hub proteins and key active compounds. Finally, we conducted animal experiments to verify the regulation of SFD on apoptosis following IS. RESULTS: There were 221 corresponding targets and 25 components related to Chinese medicine throughout the compound-target network. The core targets of SFD in the treatment of IS was tumor protein P53 (Tp53), mitogen-activated protein kinase 3 (MAPK3), MAPK1, heat shock proteins 90AA1 and alpha serine/threonine-protein kinase1. There were 221 GO items in GO function enrichment analysis and 106 signaling pathways in KEGG, mainly including negative regulation of the apoptosis process, vascular endothelial growth factor signaling pathways, NOD-like receptor signaling pathway, etc. Among them, Tp53, MAPK3, and MAPK1 were docked with small molecule compounds. Through animal research, we confirmed the effect of SFD on apoptosis following stroke. CONCLUSION: This study demonstrates that SFD can treat IS through multiple targets and pathways, and provides new perspectives for exploring the core targets and mechanisms of SFD against IS.

Drugs, Chinese Herbal↗

PubMed2026

Comparative Characterization of σ32-Dependent Promoters for the Heat-Inducible Expression of FAST-PETase in Escherichia coli.

Efficient regulation of recombinant enzyme expression is an important consideration for the development of microbial biocatalysts. Heat-inducible promoters regulated by the alternative sigma factor σ32 provide an inducer-free strategy for controlling gene expression in Escherichia coli. In this study, four σ32-dependent promoters (PdnaK, PgrpE, PibpA, and PclpB) were comparatively characterized using the PET-degrading enzyme FAST-PETase fused to superfolder green fluorescent protein as a model recombinant protein. Promoter performance was evaluated based on basal leakage, induction kinetics, and expression strength following heat induction. Among the promoters examined, PdnaK exhibited the strongest heat-inducible expression and was dissected to examine the autonomous and combinatorial behavior of its promoter-derived elements. Molecular docking analysis further supported the experimental observations by showing qualitative agreement between predicted σ32-DNA interactions and promoter performance. Together, these findings provide a comparative characterization of σ32-dependent promoters and identify promoter architectures that may facilitate the development of heat-inducible recombinant enzyme expression systems in E. coli.

Escherichia coli↗

PubMed2025

Genomic mapping of diabetic kidney disease biomarkers and identification of potential inhibitors through virtual screening.

BACKGROUND: Diabetic kidney disease (DKD) is a common and serious complication of diabetes mellitus, marked by a multifactorial pathogenesis and the absence of sensitive diagnostic biomarkers. Identifying novel molecular targets and therapeutic options is essential to improve early diagnosis and treatment outcomes. METHODS: To uncover potential biomarkers and therapeutic candidates, we performed an integrated genomic analysis using microarray and RNA-seq datasets from the Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA) databases. Differentially expressed genes (DEGs) were identified and subjected to protein-protein interaction (PPI) network analysis. Key genes were further explored through virtual screening of an FDA-approved compound library using molecular docking techniques. Drug-likeness was assessed via Lipinski's rule of five. RESULTS: A total of 40 DEGs were identified, among which ISCU (downregulated; involved in iron-sulfur cluster biogenesis) and AP1S2 (upregulated; associated with vesicular trafficking) emerged as potential biomarkers. PPI analysis revealed their involvement in critical DKD-related pathways, such as extracellular matrix remodeling and oxidative stress. Virtual screening identified six FDA-approved compounds with high binding affinity (≤-7.96 kcal/mol) to ISCU, notably ZINC000001576020, all of which complied with Lipinski's rule. CONCLUSIONS: This in-silico study nominates ISCU and AP1S2 as candidate diagnostic biomarkers for DKD and identifies computationally prioritized inhibitors targeting ISCU. These findings require experimental validation but provide a molecular framework for precision diagnosis and therapeutic development. These findings offer new molecular insights that could inform precision diagnosis and personalized treatment strategies for diabetic kidney disease.

Diabetic Nephropathies↗

PubMed2026

GPER and EGFR cross-talk highlight aldosterone- and MR antagonist-induced NO production in cultured endothelial cells.

INTRODUCTION: Aldosterone induces rapid, non-genomic vasodilation of the rat mesenteric vasculature, and mineralocorticoid receptor (MR) antagonists are widely used in cardiovascular disease, yet their pharmacological profiles beyond classical MR blockade remain unclear. We examined whether the G protein-coupled estrogen receptor (GPER/GPR30), functionally coupled to the epidermal growth factor receptor (EGFR), accounts for the rapid endothelial nitric oxide (NO) component of aldosterone action, and whether MR antagonists display intrinsic GPER-linked activity. METHODS: Aldosterone-induced vasodilation was assessed in isolated perfused rat mesenteric arterial beds precontracted with noradrenaline, and NO production was quantified in primary mesenteric endothelial cell cultures by DAF-FM fluorescence with validated vehicle controls. The mechanisms engaged by spironolactone, eplerenone and finerenone were interrogated with selective pharmacological tools and by endothelium removal. Ligand recognition was explored by molecular docking in a comparative model of the rat GPER built on the human GPER cryo-EM template. RESULTS: Aldosterone elicited concentration-dependent endothelial NO production (EC50 = 2.26 ± 0.3 nM) and vasodilation (EC50 = 0.9 ± 0.2 nM) that were closely correlated (R2 = 0.969, p < 0.01). All three MR antagonists blocked the aldosterone responses, yet each also evoked intrinsic, concentration-dependent NO production in the absence of aldosterone, eplerenone and spironolactone showing greater intrinsic efficacy than finerenone. Pretreatment with 100 nM of the GPER antagonist G-36 or 100 nM AG-1478 significantly reduced both aldosterone-induced DAF-NO signaling and vasodilation, whereas endothelium removal or L-NAME converted vasodilation into vasoconstriction. Aldosterone signaling additionally required PI3K, PKA and IP3 receptor-gated Ca2+ mobilization. Docking identified plausible receptor-engaging poses, with steroidal ligands converging on a shared cavity and finerenone adopting a distinct binding mode. DISCUSSION: MR antagonists elicit endothelial NO production through a G-36-sensitive, GPER-linked pathway functionally coupled to EGFR signaling, rather than acting as pure competitive antagonists in this context. Because recent cryo-EM work reveals a non-canonical extracellular GPER architecture, the docking results are interpreted as structurally plausible interaction scenarios rather than definitive orthosteric assignments; whether the behaviour reflects direct partial agonism at GPER or an indirect, GPER-dependent mechanism remains to be established by direct-binding studies. These findings expand current understanding of MR antagonist pharmacology.

GPER/GPR30↗

PubMed2025

Decoding the PTTG family's contribution to LUAD pathogenesis: a comprehensive study on expression, epigenetics, and therapeutic interventions.

BACKGROUND: Lung adenocarcinoma (LUAD) stands as a prevalent malignancy, yet its pathology remains incompletely comprehended. METHODS: In this comprehensive study, we explored the roles of the pituitary tumor-transforming gene (PTTG) family, including PTTG1, PTTG2, and the pseudogene PTTG3P in lung adenocarcinoma (LUAD). Employing a multi-faceted approach, we conducted in-depth analyses using clinical samples and expression datasets. RESULTS: Our findings revealed a significant up-regulation of PTTG family genes in LUAD cell lines and tissue samples compared to adjacent normal controls, suggesting their potential as diagnostic biomarkers. Through promoter methylation and mutational analyses, we uncovered regulatory mechanisms influencing PTTG gene expression. The exploration of the PTTG family's impact on LUAD patient survival demonstrated their association with adverse outcomes, emphasizing their potential prognostic relevance. Moreover, functional assays demonstrated that the knockdown of PTTG1 and PTTG2 genes resulted in the reduction of cell proliferation, colony formation, and cell migration abilities in A549 and H1975 LUAD cells. Furthermore, our investigation extended to therapeutic avenues, where we identified Calcitriol as a potential drug within the DrugBank database to down-regulate PTTG genes. Molecular docking analyses provided insights into the strong interaction between Calcitriol and PTTG1/PTTG2 proteins, laying the groundwork for further exploration of Calcitriol in LUAD treatment. CONCLUSION: In conclusion, this study contributes a comprehensive understanding of the PTTG family's involvement in LUAD, shedding light on their diagnostic, prognostic, and therapeutic implications.

Humans↗

PubMed2026

Exploring the substrate promiscuity and functional residues of UGT73 family enzymes in Entada phaseoloides.

Flavonoid glycosides and triterpenoid saponins are bioactive plant metabolites with broad applications in food, medicine, and agriculture. These compounds are typically synthesized through glycosylation catalyzed by uridine diphosphate-dependent glycosyltransferases (UGTs). In this study, phylogenetic analysis across multiple species revealed a lineage-specific expansion of the UGT73 family in legumes such as Entada phaseoloides and Glycine max. The genome of the medicinal legume E. phaseoloides was re-annotated using integrated Oxford Nanopore Technologies and Illumina transcriptomic data to identify target genes. Four expanded UGT73 family genes were selected and functionally characterized. UGT73AA6 specifically glycosylates flavonoids, while UGT73CG48 and UGT73CG49 catalyze glycosylation of both flavonoids and pentacyclic triterpenoids. UGT73CG49 exhibits higher catalytic activity for the glucosylation of flavonoids and pentacyclic triterpenes compared to its xylosylation activity. Structural modeling and molecular docking identified key active sites, and site-directed mutagenesis revealed Gly194 as a critical residue enhancing catalytic activity in UGT73CG49. This study provides new insights into the functional evolution and metabolic versatility of the UGT73 family in legumes. The identification and engineering of UGT73 genes from E. phaseoloides lay a foundation for future applications in biosynthetic pathway engineering and the industrial production of high-value glycosides.

Substrate Specificity↗

PubMed2026

Insights into the mechanism of enhanced tetramethylpyrazine production in dehulled adlay fermented by Bacillus subtilis BJ3-2.

Tetramethylpyrazine (TTMP) is a vital bioactive alkaloid and characteristic flavor compound in fermented foods. Our previous study found that fermentation of adlay by Bacillus subtilis BJ3-2 efficiently accumulates TTMP, whereas the underlying high-yield mechanism remains unclear. This study investigated the fermentation characteristics, gene transcription and protein expression of B. subtilis BJ3-2 in dehulled adlay (BDA) and soybean (BSB), respectively, and elucidated the mechanism responsible for high-yield TTMP production. The results showed that glutamate, leucine and phenylalanine were major free amino acids in BDA. The TTMP yield in BDA at 48 h (6.11 mg/g dry weight) was 360-fold higher than that in BSB. Transcriptomic and proteomic analysis demonstrated that compared with the soybean substrate, dehulled adlay substrate significantly up-regulated the expression of alsSD and ilvBH genes and their encoding proteins in B. subtilis BJ3-2, which were involved in C5-branched dibasic acid metabolism, 2-oxocarboxylic acid metabolism, and valine, leucine and isoleucine biosynthesis. Meanwhile, acetoin degradation was inhibited by down-regulating acetoin dehydrogenase complex (acoABCL) in citrate cycle, glycolysis/gluconeogenesis and carbon metabolism. Additionally, nitrogen metabolism pathway was transcriptionally enhanced to guarantee sufficient ammonium supply. Notably, protein-protein interaction and molecular docking analyses revealed that acetohydroxyacid synthase (ilvBH) interacted tightly with α-acetolactate decarboxylase (alsD), potentially forming a metabolic channel for acetoin synthesis. In conclusion, the efficient synthesis of TTMP in BDA was primarily attributed to the high synthesis and low degradation of acetoin, and the moderate synthesis of ammonium/ammonia. This study provided a theoretical basis for the targeted and efficient biosynthesis of TTMP.

Bacillus subtilis↗

PubMed2026

USP10-SIRT6-PARP1 axis drives keratinocyte senescence and skin photoaging under chronic UVA exposure.

Chronic exposure to ultraviolet A (UVA) radiation is the principal environmental driver of skin photoaging, yet the upstream molecular events that commit irradiated keratinocytes to senescence remain poorly understood. Here we show that SIRT6, an NAD+-dependent protein deacetylase with established roles in genome maintenance and organismal longevity, functions as a central gatekeeper of keratinocyte homeostasis under photic stress. Using a chronic UVA irradiation model in mice together with cultured human keratinocytes, we demonstrate that UVA inflicts extensive DNA damage and G2/M cell-cycle arrest, accompanied by selective depletion of SIRT6 among all sirtuin family members. Mechanistically, UVA suppresses the deubiquitinase USP10 at both transcriptional and post-transcriptional levels, thereby licensing ubiquitin-dependent proteasomal degradation of SIRT6. The resulting SIRT6 deficiency unleashes hyperactivation of the DNA-damage sensor PARP1, amplifying genomic injury signaling and driving keratinocytes into irreversible senescence with concomitant elaboration of a broad pro-inflammatory secretory programme encompassing chemokines and cytokines. Pharmacological reactivation of SIRT6 with the selective agonist UBCS039 reverses epidermal hyperplasia, attenuates DNA damage and senescence marker accumulation, and suppresses inflammatory mediator induction both in vivo and in vitro, establishing SIRT6 loss as a causal rather than correlative event. Furthermore, molecular docking and functional validation identify osthole, a plant-derived coumarin from the medicinal herb Cnidium monnieri, as a candidate SIRT6-engaging compound that counteracts UVA-induced senescence and inflammation in keratinocytes. Collectively, these findings define a USP10-SIRT6-PARP1 signaling axis whose disruption underlies cutaneous photoaging and suggest that SIRT6-directed strategies may offer therapeutic benefit against UV-driven tissue degeneration.

Animals↗

PubMed2026

Design, synthesis and biological evaluation of hydroxybenzothiazole-linked benzothiazole/benzoxazole conjugates as potent dual α-amylase and α-glucosidase inhibitors.

The current study focuses on the synthesis and evaluation of novel Hydroxybenzothiazole-Linked Benzothiazole/Benzoxazole Conjugates to target Diabetes Mellitus (DM) by inhibiting α-amylase and α-glucosidase. Spectroscopic methods, including 1H and 13C NMR spectroscopy, were employed to confirm the structures of newly synthesized conjugates. The findings of in-vitro analysis displayed that the synthesized derivatives inhibited α-amylase and α-glucosidase enzymes with IC50 values ranging from 3.65 ± 0.20 μM to 32.15 ± 3.20 μM on α-amylase and 5.92 ± 0.80 μM to 35.60 ± 3.40 μM on α-glucosidase, in contrast to the reference drug Acarbose (α-amylase IC50 = 8.25 ± 0.80 μM; α-glucosidase IC50 = 10.75 ± 1.10 μM). Among the series 9a-9f and 10a-10f, analogs 10 f, 10b, 9b, and 9e displayed superior anti-diabetic activity compared to the reference drug Acarbose. The inhibitory activity of these conjugates can be attributed to their favorable and stable interactions with critical amino acid residues of targeted enzymes, as revealed through molecular docking analysis. ADMET predictions and drug-likeness evaluations showed favorable pharmacokinetic features, while DFT investigations revealed electronic insights related to bioactivity. Experimental outcomes and in silico support display that these potent Hydroxybenzothiazole-Linked Benzothiazole/Benzoxazole Conjugates were comparable to an existing diabetic mellitus inhibitor while conserving an acceptable safety profile, specifying potential for further therapeutic development and optimization against diabetic Mellitus.

Benzothiazoles↗

PubMed2026

An immunoinformatics-based multi-epitope vaccine candidate confers cross-protection against two Actinobacillus pleuropneumoniae serovars.

Porcine contagious pleuropneumonia (PCP) is caused by Actinobacillus pleuropneumoniae (APP) and inflicts heavy economic losses on the swine industry. However, existing inactivated vaccines provide limited cross-protection, highlighting the need for improved vaccine strategies. In this study, we combined pangenome analysis with subtractive proteomics to screen the APP core genome and identified 11 potential antigens. Seven of them showed immunoreactivity by ELISA and Western blotting. These antigens, together with the ApxI-III toxins, were used for T and B cell epitope prediction. On this basis, a multi-epitope fusion protein MVAPP was constructed. In silico molecular docking with swine immune receptors and immune simulations suggested that MVAPP has the potential to induce immune responses. In the mouse model, that MVAPP elicited specific antibody responses, shifted the splenic T-cell subset distribution toward CD4+ T cells, and provided partial protection against challenge with strains from two serovars. In conclusion, MVAPP represents a potential multi-epitope vaccine candidate for further development against APP.

Animals↗

PubMed2026

Functional Characterization of a Novel Flavonoid O-methyltransferase From Polar Pedobacter sp. PAMC26386 and Bioactivity Assessment of Flavonoids.

Flavonoid O-methyltransferases (OMTs) catalyze the methylation of flavonoid hydroxyl groups, enhancing structural diversity and biological activity. In this study, we identified and characterized a novel Class I flavonoid OMT from the Antarctic bacterium Pedobacter sp. PAMC26386. Despite originating from a cold-adapted organism, the enzyme exhibited high catalytic activity at 55 °C and a strong preference for Co²⁺ as a cofactor. Sequence and phylogenetic analyses confirmed its classification as a flavonoid-specific OMT and revealed conserved motifs for S-adenosyl-L-methionine (SAM) binding and metal coordination. The enzyme accepted a wide range of flavonoid substrates, with quercetin and fisetin showing the highest activities. Kinetic analysis indicated greater substrate affinity for quercetin (Km = 36.55 µM) than for fisetin (Km = 49.41 µM). Whole-cell biotransformation using recombinant Escherichia coli C41 co-expressing the OMT and metK enabled efficient intracellular methylation, yielding 62.5 mg L⁻¹ of methylated quercetin and 55.5 mg L⁻¹ of 3'-O-methyl fisetin. The predicted methylation site at the 3'-hydroxyl of fisetin, determined by molecular docking, was confirmed by NMR spectroscopy. Notably, the previously reported 3'-O-methyl fisetin showed enhanced in vitro anticancer activity against mouse breast cancer cells and selectively improved antimycobacterial activity against Mycobacterium tuberculosis compared to the parent compound. To our knowledge, this study is among the first to report the enzymatic production of 3'-O-methyl fisetin using a polar microbial OMT that is optimally active at elevated temperatures in the presence of Co²⁺. The increased bioactivity compared to the parent compounds highlights the potential of this OMT as a biocatalyst for the sustainable production of pharmaceutically relevant methylated flavonoids.

Flavonoids↗

PubMed2026

Discovery of the Underlying Mechanism of Ginger Juice Processed Ziziphi Spinosae Semen for Its Sedative-Hypnotic Effect on Insomnia Mice via Regulation of HPA Axis and cAMP/PKA Signaling Pathway.

Based on Traditional Chinese Medicine (TCM) theory, the efficacy and mechanism of Ginger juice processed Ziziphi Spinosae Semen (GJPZSS) for treating insomnia, particularly stress-related types, were investigated to provide empirical evidence. An insomnia model was induced in mice by DL-4-chlorophenylalanine (PCPA) and chronic tail clamping. The sedative effect was evaluated by behavioral tests. Serum components from GJPZSS were analyzed by UHPLC-Q-TOF-MS/MS, and 64 potential targets were identified. The cAMP signaling pathway was enriched as the core pathway by Kyoto Encyclopedia of genes and genomes (KEGG) analysis and was validated by molecular docking. GJPZSS was demonstrated to prolong sleep time, reduce immobility time, increase 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) levels, decrease hypothalamic-pituitary-adrenal (HPA) axis levels, and suppress neuronal death. The reduction of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the brain was also significantly inhibited. It was concluded that the sleep-improving effect of GJPZSS was mediated through the regulation of the HPA axis and the cAMP/PKA/CREB/BDNF signaling pathway.

Animals↗