Docking Analysis Research Articles

Research on the potential mechanism of ginsenoside Rg3 against gastric cancer based on network pharmacology

Gastric cancer (GC) remains one of the most prevalent malignancies worldwide, particularly in East Asia. Despite advancements in treatment strategies, the prognosis for advanced GC patients remains unsatisfactory. Ginsenoside Rg3, a key bioactive component derived from Panax ginseng, has demonstrated significant antitumor effects in various cancers, including GC. This study systematically explores the potential mechanisms underlying the therapeutic effects of Ginsenoside Rg3, on GC, employing network pharmacology and molecular docking technologies. Key target genes and signaling pathways were identified, highlighting their critical roles in tumor cell proliferation, apoptosis, and metastasis. Molecular docking analyses revealed strong binding affinities between Ginsenoside Rg3, and crucial protein targets, supporting its direct interaction and functional modulation. The findings provide valuable insights into the molecular basis of Ginsenoside Rg3's anticancer activity and underscore its potential as a promising therapeutic candidate for GC. Future research and clinical studies are encouraged to validate these mechanisms and evaluate the clinical applicability of Ginsenoside Rg3.

Inhibitory and Curative Effects and Mode of Action of Hydroxychloroquine on Botrytis cinerea of Tomato.

Gray mold is an important disease of crops and is widespread, harmful, difficult to control, and prone to developing fungicide resistance. Screening new fungicides is an important step in controlling this disease. Hydroxychloroquine is an anti-inflammatory and anti-malarial agent, which has shown marked inhibitory activity against many fungi in medicine. This study evaluated the inhibitory activity of hydroxychloroquine against several phytopathogenic fungi, finding a half-maximal effective concentration of 113.82 μg/ml against the hyphal growth of Botrytis cinerea, with significant in-vivo curative effects of 92.37% or 78.37% for gray mold on detached tomato leaves or fruits at 10.0 or 200.0 mg/ml, respectively. Ultrastructural studies indicated that hydroxychloroquine induced collapse of hyphae, with a wrinkled surface, unclear organelle boundaries, and organelle disintegration. Transcriptomic assays revealed that hydroxychloroquine could affect the expression of metabolism-related genes. Molecular docking and molecular dynamics analyses indicated that hydroxychloroquine bound to glucose-methanol-choline oxidoreductase, with low free energy value of -11.4 kcal/mol. Cell membrane permeability assays and hyphal staining confirmed that hydroxychloroquine damaged the cell membrane, causing leakage of hyphal contents and disturbing cell function. Biochemical assays indicated that hydroxychloroquine reduced the concentration of soluble proteins and reducing sugars in the hyphae. In total, hydroxychloroquine disturbed amino acid metabolism, therefore inhibiting the production of biomacromolecules, damaging the cell membrane, and restraining the growth of hyphae, and hence inhibiting gray mold on tomato. This study will explore the use of medicine in the development of agricultural fungicides and their application in managing crop diseases, providing valuable background information.

G462S substitution of AaCYP51 confers moderate resistance to tebuconazole in Alternaria alternata.

Tobacco brown spot (TBS) caused by Alternaria alternata is one of the most common diseases of tobacco in China, resulting in large loss in yield and quality. Demethylation inhibitors (DMIs) such as tebuconazole are commonly used pesticides to control TBS. However, their control effect has shown a downward trend in recent years. In this study, the occurrence and molecular mechanism of resistance to tebuconazole in Alternaria alternata were analyzed. The resistance of 63 strains of Alternaria alternata to tebuconazole was investigated with the concentration of 5 and 20 μg/mL as the identification standard, and the resistance frequency was as high as 93.65%. It was found that the target mutation from G to S at the 462nd amino acid position of CYP51 was the cause of moderate resistance to tebuconazole in A. alternata. Molecular docking analysis further confirmed that the G462S mutation of AaCYP51 decreased the binding affinity of tebuconazole to CYP51. The artificial AaCYP51-G462S transformants based on wild-sensitive GZA-24 showed resistance to tebuconazole and cross-resistance to metconazole and prothioconazole. In the present investigation, the virulence of the CYP51-G462S mutant was reduced, while mycelial growth, sporulation, and conidial germination did not change in comparison with the progenitor strain GZA-24. In addition, the mutants containing the G462S mutation in AaCYP51 exhibited decreased sensitivity to high osmotic stress stimulated by 1 M NaCl, and the capacity to respond to cell wall- and cytomembrane-damaging agents did not change in the mutants. The G462S substitution of CYP51 is the main factor for the moderate resistance to tebuconazole in A. alternata and mechanisms other than CYP51-target mutation might be involved in tebuconazole lowly resistant isolates. © 2025 Society of Chemical Industry.

Neurotensin receptor agonist PD149163 modulates LPS-induced enterocyte apoptosis by downregulating TNFR pathway and executioner caspase 3 in endotoxemic mice: insights from in vivo and in silico study.

This study was designed to evaluate the dose-dependent efficacy of neurotensin receptor-1 (NTSR1) agonist PD149163 in the amelioration of the lipopolysaccharide (LPS)-induced apoptosis in the gastrointestinal tract (GIT) of mice. PD149163 is an analogue of NTS, a GIT tri-decapeptide with anti-inflammatory and anti-oxidative effects. Swiss-albino mice (female/8 weeks/25±2.5g) were divided into six groups: control; LPS, LPS+PD149163L, and LPS+PD149163H groups were treated with LPS (0.2μmol/L/kgBW; 5 days), followed by exposure of PD149163 to LPS+PD149163L (10.6μmol/L/kgBW), and LPS+PD149163H (21.2μmol/L/kgBW) for 28 days. OnlyPD149163L (10.6μmol/L/kgBW) and onlyPD149163H (21.2μmol/L/kgBW) groups were maintained for 28 days. Both the LPS and PD149163 were given intraperitoneally. PD149163 treatment for 4 weeks alleviated the LPS-induced enterocyte apoptosis in a dose-dependent manner. LPS-induced excessive levels of caspase-3, tumour necrosis factor-α, and leptin (biomarkers of LPS-induced apoptosis) in plasma were decreased by PD149163H treatment. Moreover, LPS-induced gut oxidative stress was ameliorated by PD149163H supplementation, as evidenced by the decreased content of malondialdehyde, lipid-hydroperoxide and increased level of superoxide-dismutase, catalase. Furthermore, PD149163H mediated elevation of the plasma anti-apoptotic protein (B-cell leukaemia/lymphoma-2) along with the NTS level contributed to the modulation of LPS-induced enterocyte apoptosis, reflected in histopathology. In vivo results were substantiated with in silico molecular docking analysis that predicted the binding of PD149163-TLR4 complex, suggesting that PD149163 can act as a TLR4 modulator and inhibit the activation of TLR4. The role of PD149163 in ameliorating GIT apoptosis by its anti-apoptotic and antioxidative effects is suggested. Further research may provide significant insights into the therapeutic intervention of PD149163 in apoptosis-related diseases of GIT.

New polymorphisms of Vkork1 gene related to anticoagulant resistance of rats and mice in Italy

AbstractBACKGROUNDAnticoagulant rodenticides (ARs) are a very effective tool to control rodent pest populations. Nevertheless, AR resistance has been documented worldwide.ARs block the cycle of vitamin K, leading to the death of the animal by internal bleeding: mutations in Vkorc1 gene can cause resistance.The spreading of AR‐resistant rodents could lead to an increase of their populations, the associated diffusion of zoonotic pathogens, and to the amplified exposure of non‐target animals to ARs, thus it is important to study its diffusion widely. This study aimed to report firstly the presence of Vkorc1 mutations in synanthropic rodents from the Emilia‐Romagna region, Italy, and evaluate their role in resistance by means of molecular docking analysis.RESULTSA total of 67 animals were analyzed: 24 Rattus norvegicus, 35 Rattus rattus and eight Mus musculus. Single nucleotide polymorphisms (SNPs) associated with AR resistance, in homozygosis or heterozygosis, were detected in 6/8 mice, on codons 128 and 139, and 13/24 R. norvegicus, on codons 61 and 139, and in 10/35 R. rattus, on codon 59. Furthermore, several newly described missense mutations were detected in all the tested species: the molecular docking analysis suggests a role of some of these (e.g., I123S and F87L) in resistance to brodifacoum, both in rats and in mice.CONCLUSIONThe discovery of AR resistance SNPs in the 43.28% of tested rodents sounds as an alarm bell that requires the introduction of an integrated control approach, where ARs are not used routinely, but under specific monitoring evaluation. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Silymarin as a Therapeutic Agent for Hepatocellular Carcinoma: A Multi-Approach Computational Study

Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal form of liver cancer with limited treatment options. Silymarin, a flavonoid complex derived from milk thistle, has shown promise in liver disease treatment due to its antioxidant, anti-inflammatory, and anticancer properties. This study aims to explore the therapeutic potential of silymarin in HCC through a comprehensive in silico approach. Methods: This study employed a network pharmacology approach to identify key molecular targets of silymarin in HCC. The Genecards and Metascape databases were used for target identification and functional annotation. Molecular docking analysis was conducted on the primary silymarin components against VEGFA and SRC proteins, which are critical in HCC progression. MD simulations followed to assess the stability and interactions of the docked complexes. Results: Network pharmacology analysis identified several key molecular targets and pathways implicated in HCC. The molecular docking results revealed strong binding affinities of silymarin components to VEGFA and SRC, with Silybin A and Isosilybin B showing the highest affinities. MD simulations confirmed the stability of these interactions, indicating potential inhibitory effects on HCC progression. Conclusions: This study provides a comprehensive in silico evaluation of silymarin’s therapeutic potential in HCC. The findings suggest that silymarin, particularly its components Silybin A and Isosilybin B, may effectively target VEGFA and SRC proteins, offering a promising avenue for HCC treatment. Further experimental validation is warranted to confirm these findings and facilitate the development of silymarin-based therapeutics for HCC.

Integrating single-cell RNA-Seq and bulk RNA-Seq data to explore the key role of fatty acid metabolism in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a predominant cause of cancer-related mortality globally, noted for its propensity towards late-stage diagnosis and scarcity of effective treatment modalities. The process of metabolic reprogramming, with a specific emphasis on lipid metabolism, is instrumental in the progression of HCC. Nevertheless, the precise mechanisms through which lipid metabolism impacts HCC and its viability as a therapeutic target have yet to be fully elucidated. In the current investigation, single-cell RNA sequencing in conjunction with weighted gene co-expression network analysis (WGCNA) was utilized to delineate lipid metabolism-related genes correlated with the prognostic outcomes of hepatocellular carcinoma (HCC). Data procurement encompassed transcriptomic and clinical datasets from HCC patients, sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories. Subsequent to this, consensus clustering analysis was implemented to stratify patients into distinct subgroups, contingent upon the expression patterns of lipid metabolism genes. Further analytical procedures involved functional enrichment analysis, evaluation of immune infiltration, and examination of the mutation landscape.PTGES3 was identified as a pivotal gene associated with lipid metabolism. Subsequent to its identification, cellular communication analysis was employed to assess the immunological attributes of PTGES3 within the tumor microenvironment. The functional role of PTGES3 was further corroborated through molecular docking simulations and in vitro experimental assays. We identified 27 genes associated with lipid metabolism, 18 of which exhibited significant correlation with overall survival in HCC patients. PTGES3 emerged as a central gene, demonstrating a robust association with immune cell infiltration and unfavorable prognosis. Cellular communication analysis revealed that PTGES3 exhibits the highest communication intensity with T cells, modulating the tumor microenvironment by potentiating the FN1/CD44 + MDK/NCL signaling pathway. Elevated expression of PTGES3 was linked to immunosuppressive cascades, diminished responsiveness to immunotherapy, and inferior overall survival outcomes. Molecular docking analysis indicated that etoposide, methotrexate, and doxorubicin could effectively bind to PTGES3. In vitro experiments confirmed that PTGES3 knockdown significantly impaired the proliferation, invasion, and migration of HCC cells. This study highlights the pivotal role of lipid metabolism in HCC progression and identifies PTGES3 as a potential prognostic biomarker and therapeutic target. These findings offer new insights into the development of targeted therapies for HCC, particularly in patients with high PTGES3 expression.

Unveiling the Phytochemical Diversity and Bioactivity of Astragalus melanophrurius: A First Report Integrating Experimental and In Silico Approaches

Background: The genus Astragalus is renowned for its diverse bioactive potential, yet the chemical composition and biological properties of Astragalus melanophrurius remain inadequately explored. This study aimed to investigate the chemical profile, antioxidant capacity, and enzyme inhibitory activities of methanol extracts from various plant parts of A. melanophrurius. Methods: Methanol extracts were obtained from leaves, stems, flowers, roots, and aerial portions of A. melanophrurius. The chemical composition was determined using LC–ESI–MS/MS, focusing on key phytochemicals such as hyperoside, kaempferol, 4-hydroxybenzoic acid, and chlorogenic acid. Antioxidant activities were assessed via DPPH, ABTS, and FRAP assays, while enzyme inhibitory activities were evaluated against α-amylase and tyrosinase. In silico molecular docking analyses were conducted to explore the interactions between major compounds and target enzymes. Results: The leaf extract exhibited the highest total phenolic and flavonoid contents, correlating with superior antioxidant activities, achieving IC50 values of 16.55 mg/mL, 4.58 mg/mL, and 3.07 mg/mL in DPPH, ABTS, and FRAP assays, respectively. The root extract demonstrated notable α-amylase (IC50 = 2.99 mg/mL) and tyrosinase (IC50 = 1.34 mg/mL) inhibitory activities, suggesting potential applications in diabetes and hyperpigmentation management. Molecular docking revealed stable complexes of hyperoside and kaempferol with target enzymes, supporting their roles in observed bioactivities. Conclusions: This study highlights the bioactivity of A. melanophrurius extracts, particularly from leaves and roots, supporting their therapeutic potential. Future research should focus on isolating active compounds and conducting in vivo studies to confirm efficacy and elucidate mechanisms of action.

Mechanistic insight into neuroprotective effect of standardized ginger chemo varieties from Manipur, India in scopolamine induced learning and memory impaired mice.

Alzheimer's disease is a complex neurodegenerative disease characterized by progressive decline in cognitive function and behaviour. Ginger is the rhizome of the plant Zingiber officinale Roscoe, has been an important ingredient of many Ayurveda formulations to treat neurological disorders. The present study aims to estimate the variation of 6-gingerol content in nine different ginger samples collected from Manipur, India, investigate the neuroprotective potential of the most potent ginger sample against scopolamine-induced cognitively impaired mice, and validate the therapeutic claim by molecular docking analysis. High Performance Thin Layer Chromatography (HPTLC) analysis suggested that the sample GV6 had the highest 6-gingerol content with potent in vitro acetylcholnesterase (AChE) (IC50 = 336.10µg/mL) and butyrylcholinesterase (BChE) (IC50 = 411.73µg/mL) enzyme inhibitory activity. The neuroprotective potential of GV6 was tested in scopolamine-induced cognitively impaired mice (200 and 400mg/kg). The behavioral analysis showed that GV6 alleviated the spatial recognition, and short-term and long-term memory in the experimental mice model. GV6 significantly improved brain AChE and BChE activity, acetylcholine (ACh) level, markedly alleviated the antioxidant parameters, and reversed the neuroinflammation. Brain histopathological observations confirmed the presence of organized nerve fibers, improvement of neuronal cell density, and reverse the nucleus shrinkage. Further molecular docking analysis showed that 6-gingerol and galantamine exhibited stable interaction with AChE (-7.5 and - 7.3 kcaL/moL) and BChE (-7.3 and - 8.5 kcaL/moL). The present study emphasizes the quality-related therapeutic importance of ginger samples from Northeast India and demonstrates that administration of GV6 may improve brain cognitive functions by restoring neurotransmitter levels and inflammatory and antioxidant parameters in scopolamine-induced cognitively impaired mice.

A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors

IntroductionTo design effective small molecule inhibitors targeting the immune checkpoint PD-1/PD-L1 and to explore their inhibitory activity.MethodsIn this paper, a total of 69 PD-1/PD-L1 inhibitors with the same backbone were searched through opendatabases, and their docking mechanism with PD-L1 protein was investigatedby molecular docking method, and the active conformation of the inhibitors was explored. The biological activity of the four newly designed inhibitors was also evaluated using ELISA.ResultsThe most active molecule 58 in the dataset formed six hydrogen bonds with Phe67, Val55, Ile116 and Tyr123, while the second most active molecule 34 formed five hydrogen bonds with Phe67 and Ala121, both of which formed π-π stacking interactions with Tyr56. The analysis of the inhibitor docking results determined that the residues Tyr123, Gln66, Thr20, Met115, Asp122 and Ile116 had the greatest influence on the active conformation of the inhibitor. ELISA assays suggested that the four novel inhibitors designed had high inhibition rates, with the inhibition rate of compound N2 being as high as 68.53%.DiscussionIn this paper, we have designed and synthesized various PD-1/PDL1 inhibitors, which provide a basis for drug discovery targeting the PD-1/PDL1 signaling pathway.

Structural and functional analysis reveals the catalytic mechanism and substrate binding mode of the broad-spectrum endolysin Ply2741

ABSTRACT The emergence of antibiotic-resistant bacteria has attracted interest in the field of endolysins. Here, we analyzed the diversity of Streptococcus endolysins and identified a new endolysin, Ply2741, that exhibited broad-spectrum bactericidal activity. Our results demonstrated that Ply2741 could effectively eradicate multidrug-resistant gram-positive pathogens in vitro and in vivo. Structural analysis revealed that the bactericidal activity of Ply2741 depends on the classic “Cys-His-Asn” catalytic triad. Site-directed mutagenesis results further identified that the conserved residue Gln29, located near the catalytic triad, also contributes to the lytic activity of Ply2741. Furthermore, the key residues (R189 and W250) in the Ply2741 cell wall binding domain (CBD) responsible for binding to peptidoglycan were revealed by molecular docking and fluorescence-activated cell sorting (FACS) analysis. Ply2741 demonstrates a broad lytic spectrum, with significant bactericidal activity against Enterococcus, Staphylococcus, and Streptococcus and species. To the best of our knowledge, we found that residue Gln29 participated in the lytic activity of endolysin for the first time. Additionally, we systematically elucidate the binding mode and key residues of the Ply2741CBD. This study proposes Ply2741 as a potential antibiotic substitute and provides a structural basis for the modification and design of endolysins.

Exploring target selectivity in designing and identifying PI3Kα inhibitors for triple negative breast cancer with fragment-based and bioisosteric replacement approach

Triple-negative breast cancer (TNBC) is one of the most fatal malignancies in the world, accounting for 42% of all deaths due to metastasis. The significant development is hindered by the multi-drug resistance and poor patient compliance. PIK3CA gene mutation is one of the important causes of TNBC, which causes dysregulation of the cell cycle and cell proliferation. PI3Kα selective inhibition can decrease the TNBC by a significant level with minimal off-target effects. Novel compounds with high selectivity towards PI3Kα are crucial for treating TNBC. After extensive literature analysis, it was observed that fragment-based drug discovery, combined with structure-based virtual screening and bioisosteric replacement strategy, could provide a novel way for hit-to-lead optimization. The present study focussed on the fragment-based direct linking of 11269 moieties of the ChemDiv fragment library, - to generate novel moieties and further screened them using molecular docking, MMGBSA, and target selectivity analysis. Further, the top 2 moieties – Djh1 and Djh2 were selected after MMGBSA analysis and target selectivity prediction towards kinase. Further induced fit docking (IFD) analysis, DFT analysis, and MD simulation were employed to establish that – Djh1 and Djh2 could act as potential hit molecules for selective inhibition of PI3Kα. Further bioisosteric replacement, docking analysis, and target selectivity analysis were performed with the bioisosteres. The top two bioisosteres of Djh1 – Compound 10, Compound 06 represented excellent efficacy and selectivity towards PI3Kα in the treatment of TNBC after analysis of ADMET analysis. Further, in vitro and in vivo analysis might prove the effectiveness of the hit compounds.

Sesamin targets ClpP which attenuates virulence of S. aureus and protects mice from fatal pneumonia induced by MRSA.

The aim of this study was to identify sesamin as a Casein hydrolase P (ClpP) inhibitor and to determine whether it could attenuate the virulence of methicillin-resistant Staphylococcus aureus (MRSA). Through fluorescence resonance energy transfer (FRET) screening, a natural compound sesamin demonstrated a significant inhibitory effect on ClpP enzyme activity with an IC50 of 20.62μg/mL. Sesamin suppressed the expression of virulence factors of MRSA such as α-hemolysin (Hla) and Panton-Valentine leucocidin (PVL) by protein immunoblotting. Thermal shift assay (TSA) and cellular thermal shift assay (CETSA) showed that sesamin could bind to ClpP and enhance the thermal stability of ClpP. Furthermore, the binding affinity between sesamin and ClpP was determined by surface plasmon resonance (SPR) with a KD value of 7.18×10-6M. Molecular docking, dynamics simulations and point mutation analysis confirmed the stability of the sesamin-ClpP complex with a -10.184kcal/mol total binding energy and identified PHE-174 in ClpP as a key binding site. In mice pneumonia model, sesamin combined vancomycin treatment markedly reduced the pathogenicity of MRSA-infected mice, offering protection against fatal lung infections. Overall, these findings validate sesamin as a promising compound that targets ClpP, reducing virulence factor expression, that holds potential as a hit compound against MRSA infections.

Hepatotoxicity of Three Common Liquid Crystal Monomers in Mus musculus: Differentiation of Actions Across Different Receptors and Pathways.

Liquid crystal monomers (LCMs) of different chemical structures were widely detected in various environmental matrices. However, their health risk evaluation is lacking. Herein, three representative LCMs were selected from 74 LCM candidates upon literature review and acute cytotoxicity evaluation, then Mus musculus were exposed to the three LCMs for 42 days at doses of 0.5 and 50 μg/kg/d to investigate hepatotoxicity and mechanisms. Phenotypic and histopathological results showed that the three LCMs (DTMDPB, MeO3bcH, and 5OCB) induced hepatomegaly, and only 5OCB induced fatty liver. DTMDPB and MeO3bcH decreased the total cholesterol (TCHO) and triglyceride (TG) content, whereas 5OCB increased the TCHO, TG, and alanine aminotransferase levels. Transcriptome and molecular docking analysis revealed that DTMDPB induced hepatotoxicity by agonizing the farnesoid X receptor, resulting in the disruption of unsaturated fatty acid biosynthesis, ascorbic acid and antioxidant pathways, and circadian clock homeostasis. MeO3bcH promoted inflammation and altered unsaturated fatty acid, primary bile acid biosynthesis, and circadian rhythm by antagonizing the aryl hydrocarbon receptor. 5OCB antagonized peroxisome proliferator-activated receptors, leading to fatty liver caused by the disruption of steroid, cholesterol, and terpenoid backbone biosynthesis pathways. This study provides references for understanding the hepatotoxicity of LCMs with different structures and the selection of priority control LCMs.

Exploration of Novel Therapeutic Targets for Breast Carcinoma and Molecular Docking Studies of Anticancer Compound Libraries with Cyclin-dependent Kinase 4/6 (CDK4/6): A Comprehensive Study of Signalling Pathways for Drug Repurposing.

This study aims to identify and evaluate promising therapeutic proteins and compounds for breast cancer treatment through a comprehensive database search and molecular docking analysis. Breast cancer (BC), primarily originating from the terminal ductal-lobular unit of the breast, is the most prevalent form of cancer globally. In 2020, an estimated 2.3 million new cases were reported, resulting in approximately 685,000 deaths. Mutations in the BRCA1 and BRCA2 genes are well-established in hereditary breast cancer. The identification of effective therapeutic proteins for BC remains a complex and evolving area of research. This study aims to identify and evaluate promising therapeutic proteins and compounds specific to breast cancer through a comprehensive database search and molecular docking analysis. A rigorous search was conducted within the National Cancer Institute (NCI), NCI Metathesaurus, SIGnaling Network Open Resource (SIGNOR), Human Protein Atlas (HPA), and the Human Phenotype Ontology (HPO) to shortlist proteins linked to BC (CUI C0678222). Recent studies were reviewed to understand the administration of CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) combined with endocrine therapy for HR-positive and HER2-negative breast cancer. Anticancer compound libraries available at ZINC and PubChem were analyzed. Compounds were evaluated based on their binding energies with CDK4 protein, a rationally selected druggable target. Key proteins linked to breast cancer were identified through database searches. Proliferation, apoptosis, and G1/S transition pathways were frequently found dysregulated in breast cancer. ZINC13152284 exhibited the strongest binding energy at -10.9 Kcal/mol, followed by ZINC05492794 with a binding energy of -10.4 Kcal/mol. Preexisting drugs showed lower binding energies with the CDK4 protein. The study highlights the importance of drug repurposing as a strategy for the safe and effective treatment of breast cancer. Synthetic inhibitors often cause severe side effects, emphasizing the need for novel targets and compounds with better therapeutic profiles. Molecular docking identified promising compounds from the ZINC database, suggesting potential new avenues for breast cancer therapy.

WITHDRAWN: Design and Synthesis of Novel Phthalazine Scaffolds Linked to 1,3,4-oxadiazolyl-1,2,3-triazoles as Potent Anticancer Agents: A Computational Docking Analysis

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In vitro and molecular docking evaluation of black sesame seeds' anti-prostate cancer and antioxidant activity processed by nine steaming nine drying

Black sesame seeds, known for their rich flavor and medicinal properties, hold significant potential as natural therapeutics against prostate cancer, a major health challenge for men today. This study explores the traditional processing technique of nine cycles of steaming and drying, which enhances the bioactive potential of these seeds. The impact of this processing on the antioxidant and anti-prostate cancer properties of black sesame seeds was systematically investigated, focusing on the key lignans, sesamin and sesamolin. HPLC was utilized to analyze the content ratios of sesamin and sesamolin, while DPPH and FRAP assays evaluated antioxidant capabilities, and MTT assays assessed anti-cancer properties against DU145 cells. Findings reveal that three cycles of steaming and drying significantly enhance antioxidant and anti-cancer activities against DU145, achieving peak concentrations of sesamin and sesamolin of 21.583% and 14.991%, respectively, with an optimal ratio of 1.4397:1. The superior antioxidant and anti-prostate cancer activity of this sample is attributed to optimal processing conditions that maximize the stability and extraction of bioactive compounds, particularly non-lignan antioxidants, while minimizing degradation; this is likely enhanced by the interplay between various phytochemicals and the effects of thermal processing on cellular structure. Processed seeds consistently outperformed raw seeds—except for those subjected to a single cycle. Additionally, molecular docking analyses revealed compelling interactions between sesamin and sesamolin and key proteins implicated in prostate cancer (FYN, ITGB3, PDGFRA, PDGFRB, and PIK3R1), demonstrating higher LibDock scores than the standard anti-cancer drug 5-fluorouracil. This research highlights the exceptional antioxidant and anti-cancer potential of black sesame seeds, particularly through the three-steaming and three-drying method, emphasizing the importance of the sesamin to sesamolin ratio in developing future anti-cancer therapeutics.

New Brusatol Derivatives as Anti-Settlement Agents Against Barnacles, Targeting HSP90: Design, Synthesis, Biological Evaluation, and Molecular Docking Investigations

The increasing challenge of marine biofouling, mainly due to barnacle settlement, necessitates the development of effective antifoulants with minimal environmental toxicity. In this study, fifteen derivatives of brusatol were synthesized and characterized using 13C-NMR, 1H-NMR, and mass spectrometry. All the semi-synthesized compounds obtained using the Multi-Target-Directed Ligand (MTDL) strategy, when evaluated as anti-settlement agents against barnacles, showed promising activity. Compound 3 exhibited the highest anti-settlement capacity, with an EC50 value of 0.1475 μg/mL, an LC50/EC50 ratio of 42.2922 (>15 indicating low toxicity), and a resuscitation rate of 71.11%, while it showed no significant phenotypic differences in the zebrafish embryos after treatment for 48 h. The toxicity screening of zebrafish also demonstrated the low ecotoxicity of the selected compounds. Furthermore, homology modeling of the HSP90 structure was performed based on related protein sequences in barnacles. Subsequently, molecular docking studies were conducted on HSP90 using these newly synthesized derivatives. Molecular docking analyses showed that most activated derivatives displayed low binding energies with HSP90, aligning well with the biological results. They were found to interact with key residues in the binding site, specifically ARG243, TYR101, and LEU73. These computational findings are anticipated to aid in predicting the enzyme targets of the tested inhibitors and their potential interactions, thus facilitating the design of novel antifoulants in future research endeavors.

Design, Synthesis, and Biological Assessment of Novel Aminobenzidazole Agonists Targeting the Stimulator of Interferon Genes (STING) Receptor Signaling Pathway for Oncology Immunotherapy.

The activation of the STING-mediated signaling pathway leads to the secretion of type I interferon (IFN) and the activation of tumor-specific T cells. STING, a pattern recognition receptor located on the endoplasmic reticulum membrane of immune cells, binds with endogenous cyclic dinucleotides. STING undergoes phosphorylation, triggering the STING-TBK1-IRF3 pathway and NF-κB pathway, resulting in the release of IFN-β and other pro-inflammatory cytokines, ultimately enhancing the activation of tumor-specific T cells. This mechanism serves to complement the limitations of immune checkpoint inhibitors and enhances the efficiency of the immune response. This study selected benzimidazole compounds GSK and SR-717, which exhibit promising potential as patented medicines, as our lead compounds. Aiming to address the challenges associated with the short half-life of benzimidazole compounds and the limited molecular activity of SR-717, we designed and synthesized a series of STING agonists (compounds 6~29). The compound 17 showed excellent agonistic activity on hSTING protein in vitro. The cytotoxicity tests of all the synthesized compounds were performed in vitro. Performed in vivo pharmacokinetic studies on the most promising compounds and conducted molecular docking analyses.

Unravelling the anti-inflammatory activity of Cyperus rotundus essential oil through gas chromatography-mass spectrometry analysis, network pharmacology, and molecular docking approaches

Cyperus rotundus rhizome is used in the traditional system of medicine to treat various diseases. The rhizomes of this plant are traditionally used as medicine for treatments of stomach pain, bowel disorders, and inflammatory pain. The present study aims to characterize the chemical constituents of the C. rotundus rhizomes essential oil (CREO) and to evaluate its possible mechanism of action as an anti-inflammatory agent by an integrative approach of gas chromatography-mass spectrometry (GC-MS), network pharmacology, and molecular docking analysis. The compound-target-disease network revealed cubenol, gamma murolene, cyperotundone, delta selinene, alpha copaene, alpha pinene, and beta caryophyllene are core compounds with higher degree values. Protein-protein interaction analysis revealed IL1B, IL10, IL6, PTGS2, TNF, and STAT3 as hub targets. A total of 1000 biological processes, 142 cellular components, and 241 molecular functional pathways were enriched. Molecular docking analysis revealed that hub compounds and protein targets had strong binding affinity between them. The top two docked poses with the lowest binding energy were identified as PTGS2-Cubenol and IL10-Gamma murolene with binding energies of -7.9 and -7.2 kcal/mol, respectively. A molecular dynamics study revealed that the PTGS2-Cubenol and IL10-Gamma murolene complex had a good amount of deformability. These results demonstrated that CREO can act on numerous proteins and pathways to form a systematic pharmacological network, and they can be considered as a candidate drug for treating inflammatory-related disorders