Docking Studies Research Articles

Evaluation of the Role of Tanshinone I in an In Vitro System of Charcot-Marie-Tooth Disease Type 2N.

Charcot-Marie-Tooth disease type 2N (CMT2N) is an inherited nerve disorder caused by mutations in the alanyl-tRNA synthetase (AlaRS) gene, resulting in muscle weakness and sensory issues. Currently, there is no cure for CMT2N. Here, we found that all five AlaRS mutations in the aminoacylation domain can interact with neuropilin-1 (Nrp1), which is consistent with our previous findings. Interestingly, three of these mutations did not affect alanine activation activity. We then performed a high-throughput screen of 2000 small molecules targeting the prevalent R329H mutant. Using thermal stability assays (TSA), biolayer interferometry (BLI), ATP consumption, and proteolysis assays, we identified Tanshinone I as a compound that binds to and modifies the conformation of the R329H mutant and other CMT-related AlaRS mutants interacting with Nrp1. Molecular docking and dynamic simulation studies further clarified Tanshinone I's binding mode, indicating its potential against various AlaRS mutants. Furthermore, co-immunoprecipitation (Co-IP) and pull-down assays showed that Tanshinone I significantly reduces the binding of AlaRS mutants to Nrp1. Collectively, these findings suggest that Tanshinone I, by altering the conformation of mutant proteins, disrupts the pathological interaction between AlaRS CMT mutants and Nrp1, potentially restoring normal Nrp1 function. This makes Tanshinone I a promising therapeutic candidate for CMT2N.

New Phytol Derivatives with Increased Cosmeceutical Potential.

Natural compounds are widely incorporated into cosmetic products for many purposes. Diterpenes often function as fragrances, enhancing the sensory experience of these formulations. However, current trends in cosmetic science aim to develop multifunctional products, where compounds traditionally used for texture or fragrance also possess biological activities that contribute to the product's efficacy. In this context, this study focuses on synthesizing derivatives of phytol-a compound already presents in cosmetic formulations-to enhance its anti-aging properties. The derivatives were synthesized through esterification with substituted benzoic and cinnamic acids, known for their antioxidant and enzyme inhibition properties. Reaction yields ranged from 91.0% to 5.2%, depending on the substituents in acid derivatives. The structures of the synthesized compounds were confirmed through NMR and MS techniques. Both the natural and newly synthesized derivatives were evaluated for their cosmeceutical potential using antioxidant assays and inhibition assays for tyrosinase, elastase, collagenase, and hyaluronidase. This work presents the first report of the synthesis and cosmetic evaluation of several of these derivatives. Comparing with phytol (1), which presented an IC50 of 77.47 µM, four of the derivatives presented improved tyrosinase inhibitory activity, with phytyl 4-methoxybenzoate being the most active (IC50 = 27.9 µM), followed by phytyl benzoate with an IC50 of 34.73 µM. Substitutions at other positions on the aromatic ring were less effective. Molecular docking studies confirmed that the modifications potentiated a stronger interaction between the synthesized compounds and tyrosinase.

Broad-Spectrum Antiviral Agents against SARS-CoV-2 Variants Inhibit the Conserved Viral Protein Nsp1-RNA Interaction.

The ongoing global threats posed by COVID-19 pandemic, catalyzed by SARS-CoV-2, underscores the pressing need for effective antiviral strategies. The viral non-structural protein 1 (Nsp1) significantly influences pathogenicity by impeding host protein expression and enhancing viral RNA translation through its interaction with the stem-loop 1 (SL1) in the 5' untranslated region (UTR). We have developed a novel dual-luciferase reporter assay, designed to investigate the critical Nsp1-SL1 interaction, and identified P23E02 as a potential inhibitor. Our investigation, combining molecular docking studies and alanine mutagenesis, has unveiled that P23E02 disrupts Nsp1-40S ribosomal subunit interaction, liberating translational inhibition and empowering host antiviral responses. P23E02 exhibits antiviral efficacy against various sarbecoviruses, making it a promising candidate for combatting COVID-19 and related diseases. This study underscores the therapeutic potential of targeting the Nsp1/SL1 axis and lays the foundation for innovative antiviral interventions, ultimately fortifying global preparedness against future viral threats.

LC-MS/MS Profiling, Biological Activities and Molecular Docking Studiesof Simmondsia Chinensis Leaves.

This study aimed to assess the biological activities of Tunisian Simmondsia chinensis and characterize their potential bioactive compounds. Different extracts of S. chinensis were tested for their antioxidant, antibacterial, anti α-amylase, and anti-acetylcholinesterase activities through in vitro assays. The methanolic extract exhibited the highest levels of antioxidant activity and total phenolic content (976.03 GAE/g extract) compared to the other extracts. Additionally, it demonstrated a substantial anti-acetylcholinesterase activity (PI= 75%) and potent antibacterial property, particularly against Enterococcus faecalis, Listeria monocytogenes, Bacillus cereus, Bacillus subtilis, and Salmonella enterica. The IC50 values of ethyl acetate and methanolic extracts against α-amylase were 42 μg/mL and 40 μg/mL, respectively, indicating potent anti-diabetic effects. HPLC-ESI-MS/MS analyses identified flavonoids and lignans as the major phenolic compounds in the methanolic extract. To better comprehend the mechanisms behind inhibitory effects on α-amylase and acetylcholinesterase enzymes, a molecular docking study was conducted. Consequently, these findings indicate that S. chinensis is a highly valuable natural resource with potential industrial applications.

Homology modelling, molecular docking studies and synthesis of aminopyrimidines as inhibitors for deoxynucleoside kinase analogues in cancer chemoprevention

The development of alternative anticancer agents with minimal side effects has become more critical due to the rising recurrence of mammalian malignancies and the severe side effects of chemotherapeutic treatments. Kinases are an essential target for neostatic impact as they play an important role in the modulation of growth factor signalling. Our work aims to screen novel nine-series of thiazole-based aminopyrimidines and sulphaminopyrimidines against the enzymes mitochondrial thymidine kinase 2, deoxyguanosine kinase (2OCP), deoxycytidine kinase (2QRN) and thymidylate kinase (1E2Q) by molecular docking, synthesise and to study their in vitro inhibitory studies. The synthesised compounds were characterised by Infrared, Nuclear magnetic resonance and Mass spectroscopy. In silico studies, compound 4c stands out among the series, with a reported docking score ranging from −6 to −8 Kcal/mol against all the analogue kinases. The in vitro cytotoxicity assay against human small-cell lung carcinoma (A-549) has shown that 5c (IC50 = 53.9 µM) has an excellent cytotoxic effect over 4c (IC50= 68.68 µM). The reason might be the presence of the benzene sulphonamide group, which enhances their anticancer action. To conclude, the compounds 4c and 5c were found to be potent inhibitors of the deoxynucleoside kinases. In vivo studies must further verify these to prove their potent neostatic effect.

Development of a selective COX-2 inhibitor: from synthesis to enhanced efficacy via nano-formulation.

Non-steroidal anti-inflammatory drugs NSAIDs are widely used for managing various conditions including pain, inflammation, arthritis and many musculoskeletal disorders. NSAIDs exert their biological effects by inhibiting the cyclooxygenase (COX) enzyme, which has two main isoforms COX-1 and COX-2. The COX-2 isoform is believed to be directly related to inflammation. Based on structure-activity relationship (SAR) studies of known selective COX-2 inhibitors, our aim is to design and synthesize a novel series of 2-benzamido-N-(4-substituted phenyl)thiophene-3-carboxamide derivatives. These derivatives are intended to be selective COX-2 inhibitors through structural modification of diclofenac and celecoxib. The compound 2-benzamido-5-ethyl-N-(4-fluorophenyl)thiophene-3-carboxamide VIIa demonstrated selective COX-2 inhibition with an IC50 value of 0.29 μM and a selectivity index 67.24. This is compared to celecoxib, which has an IC50 value of 0.42 μM and a selectivity index 33.8. Molecular docking studies for compound VIIa displayed high binding affinity toward COX-2. Additionally, the suppression of protein denaturation with respect to albumin was performed as an indicative measure of the potential anti-inflammatory efficacy of the novel compounds. Compound VIIa showed potent anti-inflammatory activity with 93% inhibition and an IC50 value 0.54 μM. In comparison, celecoxib achieved 94% inhibition with an IC50 value 0.89 μM. Although molecule VIIa demonstrated significant in vitro anti-inflammatory activity, adhered to Lipinski's "five rules" (RO5) and exhibited promising drug-like properties, it showed indications of poor in vivo activity. This limitation is likely due to poor aqueous solubility, which impacts its bioavailability. This issue could be addressed by incorporating the drug in niosomal nanocarrier. Niosomes were prepared using the thin-film hydration technique. These niosomes exhibited a particle size of less than 200 nm, high entrapment efficiency, and an appropriate drug loading percentage. Transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies revealed that the niosomes were spherical and demonstrated compatibility of all of its components. The drug release study indicated that the pure drug had limited practicality for in vivo use. However, incorporating the drug into niosomes significantly improved its release profile, making it more suitable for practical use.

Novel Bis-thiazoles with pyridine and 1,4-Dihydropyridine linkers as potential anti-Alzheimer agents

A series of bis-hydrazonothiazoles with pyridine and 1,4-dihydropyridine linkers was synthesized using 2,2′-[(2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)]bis(hydrazine-1-carbothioamide) and 2,2′-[(2,6-dimethylpyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)]bis(hydrazine-1-carbothioamide) as starting materials, which were reacted with 1-aryl-2-bromoethanone to form the desired bis-hydrazonothiazoles. Additionally, an alternative synthetic strategy involved the simple oxidation of 1,4-dihydropyridine linkers using a mixture of aqueous sodium nitrite and acetic acid to produce pyridine linkers. The synthesized compounds were subjected to molecular docking studies against the protein 1EVE (one of the AD bio-markers) to evaluate their 3-D orientation, flexibility, and conformational changes upon binding—key factors for optimizing drug design and therapeutic efficacy. The binding affinities of the synthesized compounds ranged from −1.14 to −11.64 kcal/mol, compared to -6.78 to -10.24 kcal/mol for the reference drugs. Statistical analysis revealed no significant difference in binding affinity between Donepezil and compounds 5c, 7a, 7b, and 8a, indicating similar therapeutic potential. Differences in binding affinities among the approved drugs underscored their distinct interaction profiles with the target protein. Molecular docking and SwissADME predictions helped prioritize molecules based on drug-likeness and pharmacokinetic profiles, identifying candidates for in-vivo validation and enhancing the drug development process.

Exploring Teucrium aureo-candidum Essential Oil as a Promising Alternative to Triclosan for Targeting Enoyl-Acyl Carrier Protein Reductase: Chemical Composition, Antibacterial Activity, and Molecular Docking Study.

The chemical composition of the essential oil isolated from the aerial parts of Teucrium aureo-candidum, an endemic aromatic shrub collected from Moghrar and Djeniene Bourezg in the Nâama region (Algeria), was determined for the first time using GC/FID and GC/MS. A total of 45 constituents were identified, representing 87.73% of the oil. Characterized by unique chemical variability, it was primarily composed of sesquiterpene hydrocarbons (29.53%) and oxygenated sesquiterpenes (30.06%), with the major compounds being γ-cadinene (5.24%), δ-cadinene (4.24%), α-muurolene (4.04%), τ-muurolol (11.35%), and α-cadinol (3.30%). However, monoterpene hydrocarbons and oxygenated monoterpenes accounted for 23.98% and 1.64%, respectively, contributing to a relatively low fraction. The essential oil demonstrated notable antibacterial activity, particularly against Gram-positive bacteria. Due to safety concerns associated with triclosan, a known inhibitor of the Enoyl-Acyl Carrier Protein Reductase (FabI) enzyme, the essential oil components from this plant were explored as alternatives through a combination of experimental approaches and in silico molecular docking studies. The results revealed that α-cadinol, spathulenol, caryophyllene, and α-muurolene exhibited strong FabI inhibition, with better bioavailability and lower toxicity than triclosan, highlighting their potential in combating antibiotic-resistant bacteria.

Broad‐Spectrum Antiviral Agents against SARS‐CoV‐2 Variants Inhibit the Conserved Viral Protein Nsp1–RNA Interaction

AbstractThe ongoing global threats posed by COVID‐19 pandemic, catalyzed by SARS‐CoV‐2, underscores the pressing need for effective antiviral strategies. The viral non‐structural protein 1 (Nsp1) significantly influences pathogenicity by impeding host protein expression and enhancing viral RNA translation through its interaction with the stem‐loop 1 (SL1) in the 5′ untranslated region (UTR). We have developed a novel dual‐luciferase reporter assay, designed to investigate the critical Nsp1–SL1 interaction, and identified P23E02 as a potential inhibitor. Our investigation, combining molecular docking studies and alanine mutagenesis, has unveiled that P23E02 disrupts Nsp1–40S ribosomal subunit interaction, liberating translational inhibition and empowering host antiviral responses. P23E02 exhibits antiviral efficacy against various sarbecoviruses, making it a promising candidate for combatting COVID‐19 and related diseases. This study underscores the therapeutic potential of targeting the Nsp1/SL1 axis and lays the foundation for innovative antiviral interventions, ultimately fortifying global preparedness against future viral threats.

Design, In Silico, and In vitro Evaluation of Polymer-Based Drug Conjugates Incorporated with Derivative of Cinnamic Acid, Zidovudine, and 4-Aminosalicylic Acid against Pseudo-HIV-1.

The incorporation of anti-HIV drugs into polymer to form polymer-drug conjugates has been reported to result in improved therapeutic activity. Zidovudine, an anti-HIV drug, was explored alone and in combination with known drug molecules using polyamidoaminebased carriers. Polymer-drug conjugates incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid were prepared and evaluated for their potential efficacy in vitro against pseudo- HIV-1. Aqueous Michael addition polymerization reaction was employed to prepare the conjugates. The conjugates were incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid. They were characterized by SEM/EDX, XRD, FTIR, NMR, LC-MS, particle size analysis, in vitro analysis, computational studies, and in silico toxicity predictions. The conjugates displayed spherically shaped morphology. The in vitro findings showed that polymer-drug conjugates, T15 and T16, with a single drug were effective against pseudo- HIV-1 at high concentrations of 111.11 and 333.33 μg/mL, respectively. The molecular docking studies confirmed the in vitro results. The Swiss ADME, ProTox-II, and GUSAR (General Unrestricted Structure-Activity Relationships) revealed that these compounds are promising antiviral compounds. The prepared polymer-drug conjugates with a single drug showed promising effects against the Pseudo-HIV-1, and the conjugates displayed features that make them potential anti- HIV therapeutics that require further studies.

Structural Characteristics and DNA Groove Binding Abilities of Two Zinc BasedIsoreticularMOFs.

In this study, we have synthesized two zinc(II)-based metal-organic frameworks (MOFs) designated as [Zn(4-nvp)(bdc)]·(MeOH) (1) and [Zn2(4-nvp)2(bpdc)2]·(DMF) (2) [4-nvp = 4-(1-Naphthylvinyl) pyridine, H2bdc = 1,4-benzendicarboxylic acid and H2bpdc = 4,4'-biphenyldicarboxylic acid]. Single-crystal X-ray diffraction (SCXRD) of both compounds unveiled an interesting paddle-wheel [Zn2(O2C-C)4] secondary building unit composed of dinuclear Zn (II) centers and four dicarboxylate groups with a (4,4) square grid topology. These SBUs are interconnected giving rise to an infinite 2D layer architecture. Notably, the grid structure is composed of MeOH molecules in compound 1 and DMF molecules in compound 2, both of them arranged in a free lattice. In both compounds, 3D supramolecular architecture is ultimately formed through the stacking of 2D layers. Since the length of the bpdc ligand is higher than that of the bdc ligand, the solvent-accessible void volume is comparatively higher for compound 2. To corroborate all non-bonded interactions, Hirshfeld analysis was carried out for synthesized compounds. DNA binding application was extensively investigated through docking study. Results indicated that the synthesized compounds have strong affinities towards DNA via DNA groove binding. Henceforth, the synthesized compounds 1 and 2 would open the door for their potential applications as particular protein binders and bioactive substances.

Bioactive phytocompounds profiling and the evaluation of analgesic, anti-inflammatory, and antihyperglycemic potential of Argyreia capitiformis (Poir.) Ooststr.: A combined in vitro, in vivo, and computational investigations

Ethnopharmacological relevanceArgyreia capitiformis (Poir.) Ooststr. (Convolvulaceae) is traditionally used by the Chakma community in the hilly region of Bangladesh to treat minor disorders such as pain. Aim of the studyThis study intended to determine the secondary metabolites to identify bioactive compounds and evaluate antioxidant potential, in vitro anti-inflammatory and in vivo analgesic, anti-inflammatory, and antihyperglycemic activities of A. capitiformis along with in silico investigations. Materials and methodsChemical profiling was carried out using HPLC and GC-MS analysis. The analgesic effect was measured employing tail immersion and acetic acid-induced writhing methods. Following protein denaturation and formalin-induced paw edema, anti-inflammatory activity was studied. The antihyperglycemic potential was assessed using an oral glucose tolerance test (OGTT), while further mechanistic investigation was conducted using an alpha-glucosidase enzyme inhibitory assay. Simulations and molecular docking analyses were performed to ascertain the stability and binding affinities of the drug-protein complex. ResultsA. capitiformis ethanolic extract confirmed the presence of phenolics, alkaloids, flavonoids, terpenoids, tannins, gums, steroids, and reducing sugars. HPLC analysis revealed the presence of eight polyphenolic compounds, the most abundant of which was myricetin (64.10 ± 0.14 mg per 100 g dry extract). Moreover, the GC-MS analysis revealed twenty-four molecules, the most important of which was 2,4-bis (dimethylbenzyl)-6-t-butylphenol (9.19%). The concentrations of total flavonoids, total terpenoids, total phenolics, and total tannins were ascertained to be 142.48 mg QE/g, 173.1 mg UAE/g, 19.35 mg GAE/g, and 13.05 mg GAE/g, respectively. Furthermore, the plant extract had a total antioxidant capacity of 388 mg AAE/g. In the writhing assay, the plant extract suppressed writhing by 59.73% and 76.99% at the doses of 250 and 500 mg/kg, respectively, compared to the standard diclofenac Na 87.17%, and in the tail immersion assay, the plant extract displayed a maximum average reaction time of 1.94 and 2.40 s at the doses of 250 and 500 mg/kg, respectively as compared to the control tramadol 2.84 s at 60 min. In an in vitro anti-inflammatory assay, the plant extract possessed an IC50 of 95.51 μg/ml while diclofenac Na (standard drug) was found to be 69.50 μg/ml. Afterward, in vivo anti-inflammatory activity was observed in mice over a period, particularly after 3 h, the plant extract exerted maximum percent inflammation inhibitions of 36.36% and 45.45% at the doses of 250 and 500 mg/kg, respectively whereas ibuprofen the standard drug (100 mg/kg) exhibited 61.82%. The plant extract demonstrated antihyperglycemic activity, lowering blood sugar levels to 5.7 and 4.62 mM at doses of 250 and 500 mg/kg, respectively, as opposed to 8.58 mM in the control group. Meanwhile, the standard drug glibenclamide (5 mg/kg) dropped blood glucose levels to 2.38 mM in 60 min after glucose administration. Molecular docking (MD) and molecular dynamics simulation (MDS) studies support the stability of the protein complex responsible for exerting pharmacological activities. ConclusionA. capitiformis extract exhibited strong medicinal values supporting its traditional uses.

Computational insights into irinotecan's interaction with UBE2I in ovarian and endometrial cancers

Endometrial and Ovarian cancers are two highly prevalent and fatal reproductive diseases with poor prognoses among women. Elevated estrogen levels in Ovarian Cancer (OC) stimulate the endometrium, causing Endometrial Cancer (EC). Although numerous studies have reported the crucial genes and pathways in this cancer, the pathogenesis of this disease remains unclear. In this study, used bioinformatics tools to analyse GSE63678, GSE115810, GSE36389, GSE26712, GSE36668, GSE27651, GSE6008, GSE69429, GSE69428, GSE18521, GSE185209, GSE54388 gene expression microarray datasets for both the cancers. We analyzed the differential gene expression, functional association, and structural studies. The analysis identified crucial differentially expressed genes (DEGs) in both cancers associated with DNA damage, DNA integrity, and cell-cycle checkpoint signaling pathways. CLDN7, UBE2I, WT1, JAM2, FOXL2, F11R, JAM3, ZFPM2, MEF2C, and PIAS1 are the top 10 hub genes commonly identified in both cancer types. Only CLDN7 and F11R are upregulated, whereas the remaining hub genes are downregulated in both cancers, suggesting a common framework for contributing to tumorigenesis. Molecular docking and dynamics were performed on the UBE2I protein with Irinotecan Hydrochloride, which could serve as the new approach for treating and managing both cancers. The study reveals the common molecular pathways, pointing out the role of cell cycle and DNA damage and integrity checkpoint signaling in the pathogenesis of both cancer types. This study explored the UBE2I gene as a potential biomarker in OC and EC. Further, this study concludes that the irinotecan hydrochloride drug has higher therapeutic effects on UBE2I protein through docking and dynamics studies.

Chemical Composition, Antioxidant, Antibacterial, and Hemolytic Properties of Ylang-Ylang (Cananga odorata) Essential Oil: Potential Therapeutic Applications in Dermatology

Background/Objectives: This study investigates the chemical composition, antioxidant, antibacterial, and hemolytic properties of ylang-ylang (Cananga odorata) essential oil, with a focus on its potential therapeutic applications for dermatological diseases and the importance of transforming such bioactive properties into a stable, safe, and effective formulation. Methods/Rsults: Essential oils were extracted from flowers harvested in northern Grande Comore using hydro distillation at three different distillation times to examine the impact on yield and quality. Gas chromatographic analysis identified a complex mixture of compounds, including linalool, geranyl acetate, and benzyl benzoate. Antioxidant activity was assessed using DPPH, FRAP, TAC, and beta-carotene bleaching inhibition assays, revealing significant radical scavenging capabilities, with DPPH IC50 varying between 1.57 and 3.5 mg/mL. Antibacterial activity was tested against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa, showing promising inhibition zones and minimum inhibitory concentrations. Hemolytic tests indicated varying degrees of red blood cell damage, emphasizing the need for careful concentration management in therapeutic applications. Molecular docking studies highlighted potential therapeutic targets for dermatological conditions, identifying high binding affinities for specific compounds against proteins involved in acne, eczema, and psoriasis. Conclusions: This comprehensive analysis underscores the potential of ylang-ylang essential oil (YEOs) as a natural alternative for antimicrobial treatments and dermatological applications, with its success dependent on optimized extraction methods and precise formulation to reduce cytotoxic effects. A formulation approach is crucial to ensure controlled release, improve bioavailability, and minimize skin irritation.

Family Malvaceae: a potential source of secondary metabolites with chemopreventive and anticancer activities supported with in silico pharmacokinetic and pharmacodynamic profiles.

Cancer is the second most widespread cause of mortality following cardiovascular disorders, and it imposes a heavy global burden. Nowadays, herbal nutraceutical products with a plethora of bioactive metabolites represent a foundation stone for the development of promising chemopreventive and anticancer agents. Certain members of the family Malvaceae have traditionally been employed to relieve tumors. The literature concerning the chemopreventive and anticancer effects of the plant species along with the isolated cytotoxic phytometabolites was reviewed. Based on the findings, comprehensive computational modelling studies were performed to explore the pharmacokinetic and pharmacodynamic profiles of the reported cytotoxic metabolites to present basis for future plant-based anticancer drug discovery. All the available information about the anticancer research in family Malvaceae and its cytotoxic phytometabolites were retrieved from official sources. Extensive search was carried out using the keywords Malvaceae, cancer, cytotoxicity, mechanism and signalling pathway. Pharmacokinetic study was performed on the cytotoxic metabolites using SWISS ADME model. Acute oral toxicity expressed as median lethal dose (LD50) was predicted using Pro Tox 3.0 web tool. The compounds were docked using AutoDock Vina platform against epidermal growth factor receptor (EGFR kinase enzyme) obtained from the Protein Data Bank. Molecular dynamic simulations and MMGBSA calculations were performed using GROMACS 2024.2 and gmx_MMPBSA tool v1.5.2. One hundred forty-five articles were eligible in the study. Several tested compounds showed safe pharmacokinetic properties. Also, the molecular docking study showed that the bioactive metabolites possessed agreeable binding affinities to EGFR kinase enzyme. Tiliroside (25), boehmenan (30), boehmenan H (31), and isoquercetin (22) elicited the highest binding affinity toward the enzyme with a score of -10.4, -10.4, -10.2 and -10.1Kcal/mol compared to the reference drug erlotinib having a binding score equal to -9Kcal/mol. Additionally, compounds 25 and 31 elicited binding free energies equal to -42.17 and -42.68Kcal/mol, respectively, comparable to erlotinib. Overall, the current study presents helpful insights into the pharmacokinetic and pharmacodynamic properties of the reported cytotoxic metabolites belonging to family Malvaceae members. The molecular docking and dynamic simulations results intensify the roles of secondary metabolites from medicinal plants in fighting cancer.

Synthesis and antibacterial potential of novel thymol derivatives against methicillin-resistant Staphylococcus aureus and P. aeruginosa pathogenic bacteria.

The increasing threat of antibiotic resistance has created an urgent need for new antibacterial agents, particularly plant-based natural compounds and their derivatives. Thymol, a natural monoterpenoid phenolic compound derived from Monarda citriodora, is known for its aromatic and therapeutic properties, including antibacterial activity. This study focuses on synthesizing dihydropyrimidinone and dihydropyridine derivatives of thymol and exploring their antibacterial properties. The synthesized compounds were tested for their in vitro antibacterial potential against pathogenic microorganisms, specifically Pseudomonas aeruginosa (Gram-negative) and methicillin-resistant Staphylococcus aureus (MRSA) (Gram-positive). Among the synthesized derivatives, compound 3i (ethyl 4-(4-hydroxy-5-isopropyl-2-methylphenyl)-2-imino-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate) exhibited the most promising antibacterial activity, with minimum inhibitory concentration (MIC) values of 12.5µM against P. aeruginosa and 50.0µM against MRSA. Additionally, compound 3i demonstrated a synergistic effect when combined with vancomycin, enhancing its antibacterial efficacy. The optimum fractional inhibitory concentration index (FICI) observed was 0.10 and 0.5 for MRSA and P. aeruginosa, respectively, in combination with vancomycin. In silico analysis of the physiochemical properties of 3i indicated compliance with all drug-likeness rules. Furthermore, molecular docking studies revealed that compound 3i has a stronger binding affinity to the target protein than thymol, providing valuable insights into its potential mechanism of action.

Matrine alkaloids modulating DNA damage repair in chemoresistant non-small cell lung cancer cells

BackgroundNon-small cell lung cancer (NSCLC) presents a significant challenge in the medical field due to its high incidence and resistance to chemotherapy. Chemoresistance in NSCLC diminishes treatment efficacy and contributes to poor patient outcomes. Matrine alkaloids have shown promise in reversing chemotherapy resistance in NSCLC by targeting DNA repair mechanisms.MethodsUtilizing molecular dynamics simulations, we explored the interactions between Matrine alkaloids and DNA repair-related proteins to elucidate their impact on NSCLC cells. In vitro experiments involved treating A549/DDP cells with Matrine alkaloids to evaluate their sensitizing effects on lung cancer cells. Additionally, animal model experiments were conducted to validate the therapeutic potential of Matrine alkaloids in NSCLC treatment.ResultsOur findings demonstrate that Matrine alkaloids disrupt DNA damage repair processes in NSCLC cells, leading to increased sensitivity to chemotherapy. Molecular docking studies revealed the intricate mechanisms by which Matrine alkaloids interact with DNA repair proteins, impacting cell survival and proliferation. Both cell experiments and animal models confirmed the chemosensitizing effects of Matrine alkaloids in NSCLC treatment.ConclusionMatrine alkaloids offer a promising avenue for overcoming chemotherapy resistance in NSCLC by interfering with DNA repair pathways. This study lays a solid foundation for future clinical investigations into the potential of Matrine alkaloids as effective therapeutic agents for enhancing NSCLC treatment outcomes.

Synthesis, computational analysis, and anti-proliferative evaluation of novel bithienylbenzamidine derivatives: Towards cytostatic cancer therapeutics

Our research unveils the synthesis and characterization of four novel monocationic 2,5-diarylbithiophene derivatives 4a-d, prepared through Suzuki cross-coupling reactions and subsequent amidine formation. Density Functional Theory (DFT) calculations provide unprecedented insights into the electronic properties and structure-activity relationships of these compounds. In vitro screening against the NCI-60 cancer cell panel demonstrates remarkable anti-proliferative activities. Compound 4c emerges as a standout candidate, exhibiting potent growth inhibition across multiple cancer types, with GI50 values as low as 0.36 µM against certain ovarian cancer lines. Intriguingly, our research suggests a potential shift from purely cytotoxic towards more cytostatic behavior, potentially offering improved therapeutic windows and reduced side effects. Molecular docking studies provide evidence for the compounds' interaction with human carbonic anhydrase IX, hinting at a possible mechanism of action. This comprehensive study not only introduces a promising new class of anti-cancer compounds but also provides a rich foundation of structural, electronic, and biological data to fuel future research. The bithienylbenzamidine derivatives, particularly compound 4c, represent exciting candidates for further development in the ongoing battle against cancer.

Influence of Pyridine Entangled Novel Hybrid Quinoxaline Spirane on the Fluorescence and Absorption Spectra of Biomolecules: Molecular Docking, Pharmacokinetic, and In-Vitro Biological Investigations.

Spectroanalytical techniques are extensively employed in contemporary research to characterize compounds and assess their biological activity. The β-lactam ring containing twenty novel spiro quinoxaline-pyridine heterocyclic compounds (A - T) were synthesized and characterized using 1H NMR, 13C NMR, FT-IR, and mass spectrometry. The compounds must interact with DNA to adequately assess their potential anticancer action. Thus, their binding affinities with calf-thymus (CT) DNA and bovine serum albumin (BSA) were evaluated using a UV-visible spectrophotometer. The Kb value of compound-DNA and compound-BSA was found in the order of 0.51-2.53 M- 1 and 0.11-2.03 M- 1, respectively. Furthermore, a fluorescence quenching study was also carried out using a fluorescence spectrometer to explore DNA/BSA binding, and a partial intercalation type of binding was suggested. MTT assay was performed to evaluate the anticancer activity of the compounds. A docking study of all the compounds was performed with DNA (1 BNA), BSA (4F5S), and topoisomerase II (3QX3) using autodock vina software. SwissADME and admetSAR, two online platforms, were used to assess the pharmacokinetic profile and determine the drug-likeness of the synthesized compounds.

Identification of potential therapeutic targets for systemic lupus erythematosus based on GEO database analysis and Mendelian randomization analysis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Current treatments mainly rely on immunosuppressants, which lack specificity and pose challenges during treatment. This study aims to deeply explore the molecular pathogenic mechanism of SLE through gene expression databases (GEO) and bioinformatics analysis methods, combined with Mendelian randomization analysis, to provide key clues for new therapeutic targets. In this study, the SLE-related gene chip dataset GSE65391 was selected from the GEO database, and the data were preprocessed and statistically analyzed using R language and bioinformatics tools. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), GO, and KEGG enrichment analysis were used to screen differentially expressed genes (DEGs) for functional annotation and pathway localization. Furthermore, Mendelian randomization analysis was conducted to identify core genes closely related to SLE risk, and immune cell infiltration analysis and compound molecular docking studies were performed on the core gene ISG15. The study successfully screened 3,456 DEGs and identified core gene modules highly related to SLE through WGCNA analysis, including key genes closely related to the pathogenesis of SLE, such as STAT1, DDX58, ISG15, IRF7, and IFIH1. In particular, this study found a significant positive correlation between the ISG15 gene and SLE, suggesting that it may be a potential risk factor for SLE. Additionally, through molecular docking technology, it was discovered that the ISG15 gene can effectively bind to two compounds, genistein, and flavopiridol, which have anti-inflammatory and immunosuppressive effects, respectively. This provides new potential drug targets for SLE treatment. As an immunomodulatory cytokine, ISG15 plays a crucial role in the pathogenesis of SLE. This study found that variations in the ISG15 gene may increase the risk of SLE and exacerbate inflammatory responses and tissue damage through multiple mechanisms. Furthermore, molecular docking revealed that genistein and flavopiridol can effectively bind to ISG15, offering a new approach for SLE treatment. These two compounds, with their anti-inflammatory and immunosuppressive properties, have the potential to slow the progression of SLE by influencing the expression and function of ISG15. Through comprehensive bioinformatics analysis and Mendelian randomization analysis, this study deeply explored the molecular pathogenic mechanism of SLE and successfully identified ISG15 as a potential therapeutic target for SLE. Simultaneously, molecular docking technology revealed that two compounds, genistein and flavopiridol, have potential therapeutic effects with ISG15, providing new potential drugs for SLE treatment. These discoveries not only enhance our understanding of the pathogenesis of SLE but also provide important clues for developing new treatment strategies.