Molecular Docking Research Articles

Indoloquinoline alkaloid neocryptolepine derivative inhibits Botrytis cinerea by targeting thiamine thiazole synthase

The emergence and rapid spread of multidrug-resistant Botrytis cinerea strains pose a great challenge to the quality and safety of agricultural products and the efficient use of pesticides. Previously unidentified fungicides and targets are urgently needed to combat B. cinerea –associated infections as alternative therapeutic options. In this study, the promising compound Z24 demonstrated efficacy against all tested plant pathogenic fungi. Thiamine thiazole synthase (Bcthi4) was identified as a target protein of Z24 by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) assays. Molecular docking and enzyme activity experiments have demonstrated that Z24 can affect the function of Bcthi4. Last, mechanistic studies show that Z24 inhibits thiamine biosynthesis by binding to Bcthi4 and induces up-regulation of alternative splicing [alternative 5′ splice site (A5SS)] of the Bcthi4 gene. In conclusion, by targeting Bcthi4, Z24 has the potential to be developed as a previously unidentified anti– B. cinerea candidate.

Anticancer effects of Plantago major extract on colorectal and gastric cancer cell lines: an invitro study and molecular docking analysis.

Colorectal cancer and gastric cancer are one of the most prevalent types of cancer and are leading causes of cancer-related mortality worldwide. The chemotherapy is insufficient due to the poor targeting and affinity of drugs, low therapeutic effectiveness, and significant side effects. Consequently, developing effective therapeutic formulations is crucial for treating colorectal and gastric cancers. Plantago major (P.major) is a medicinal plant that has been investigated for medical research for cancer therapy owing to its rich phytochemical composition. This study aims to evaluate the antiproliferative activity of P.major leaf extract on NIH/3T3 fibroblast cells, AGS gastric, and Caco-2 colorectal cancer cell lines for 24 h using XTTcell viability assay. The apoptotic activity of P.major was examined by detecting caspase 3/7 level in cells. The ROS levels in cells were measured using the DCFH-DA dye. Additionally, it assesses the interaction and binding affinities of the active compounds of P.major with the overexpressed EPCAM through molecular docking. The results demonstrate a dose-dependent anticancer effect of P.major on AGS and Caco-2 cell lines by reducing cell proliferation, increasing intracellular ROS accumulation and activating the caspase 3/7 apoptosis pathway. P.major exhibited no significant cytotoxic effects on non-cancerous NIH/3T3 fibroblast cells. Molecular docking analysis confirmed the high binding affinity of active compounds in P.major, such as apigenin, aucubin, baicalein, caffeic acid, and luteolin, towards the EpCAM protein overexpressed in gastric and colorectal cancer. In conclusion, the P.major can be a promising effective therapeutic strategy for gastrointestinal cancers.

Integrative Network Pharmacology and Bulk RNA‐Seq Unveil Berberine's Modulation of Mitochondrial Function and Oxidative Stress via SOD2 in Experimental Models of Ovarian Cancer

AbstractOvarian cancer (OC) remains a formidable gynecological malignancy with limited therapeutic options and substantial side effects associated with conventional treatments. Berberine (BBR), a natural isoquinoline alkaloid, has shown promising anti‐cancer properties; however, its mechanisms of action in OC are not fully elucidated. In this study, an integrative approach is employed that combines network pharmacology, molecular docking, molecular dynamics stability analysis and bulk RNA sequencing (bulk RNA‐seq) to identify OC‐related targets of BBR. In vivo and in vitro experiments demonstrate that BBR significantly inhibited tumor growth and metastasis in a mouse peritoneal metastasis model. Moreover, it is further confirmed that BBR modulates the OC microenvironment under high‐lipid conditions by activating Superoxide Dismutase2 (SOD2), reducing lipid metabolism, and decreasing Reactive Oxygen Superspecies (ROS) levels.

Intermolecular 1,2,4-Thiadiazole Synthesis Enabled by Enzymatic Halide Recycling with Vanadium-Dependent Haloperoxidases.

The enzymatic synthesis of heterocycles is an emerging biotechnology for the sustainable construction of societally important molecules. Herein, we describe an enzyme-mediated strategy for the oxidative dimerization of thioamides enabled by enzymatic halide recycling by vanadium-dependent haloperoxidase enzymes. This approach allows for intermolecular biocatalytic bond formation using a catalytic quantity of halide salt and hydrogen peroxide as the terminal oxidant. The established method is applied to a diverse range of thioamides to generate the corresponding 1,2,4-thiadiazoles in moderate to high yields with excellent chemoselectivity. Mechanistic experiments suggest that the reaction proceeds through two distinct enzyme-mediated sulfur halogenation events that are critical for heterocycle formation. Molecular docking experiments provide insight into reactivity differences between biocatalysts used in this study. Finally, the developed biocatalytic oxidative dimerization is applied to a preparative scale chemoenzymatic synthesis of the anticancer agent penicilliumthiamine B. These studies demonstrate that enzymatic halide recycling is a promising platform for intermolecular bond formation.

Structure-based development of a covalent inhibitor targeting Streptococcus pyogenes over Staphylococcus aureus sortase A.

Sortase A (SrtA), a cysteine transpeptidase critical for surface protein anchoring in Gram-positive pathogens, represents an attractive antivirulence target. While covalent SrtA inhibitors show therapeutic potential, existing compounds lack species selectivity. Through structure-guided design, we developed T10, a covalent inhibitor selectively targeting Streptococcus pyogenes SrtA (SpSrtA) over Staphylococcus aureus SrtA (SaSrtA). Molecular docking revealed that shortening a "C=C" bond in lead compound ML346 eliminated SaSrtA inhibition due to steric hindrance from W194, while maintaining SpSrtA binding. X-ray crystallography confirmed T10's covalent modification of Cys208 in SpSrtA. T10 demonstrated two fold enhanced inhibitory potency and species-specific disruption of M-protein anchoring and biofilm formation in Streptococcus pyogenes, without affecting Staphylococcus aureus viability. In a Galleria mellonella infection model, T10 conferred potent protection against lethal infection. This work demonstrates the development of narrow-spectrum antivirulence agents through a structure-based rational strategy.

Synthesis, Antifungal Activity and In Silico Study of Novel Quinoline Thioether Derivatives Inspired by Natural Quinoline.

Inspired by natural quinoline, a series of novel quinoline derivatives containing thioether groups were designed and synthesized. All target compounds were characterized using 1H NMR, 13C NMR, and HRMS. Their antifungal activities were evaluated in vitro against ten phytopathogenic fungi. Among the synthesized compounds, 3l (4-(allylthio)-8-fluoro-2,3-dimethylquinoline) exhibited significant antifungal activity, with inhibition rates exceeding 80% against Sclerotinia sclerotiorum and Physalospora piricola at 50 μg/mL. The structure-activity relationship (SAR) analysis revealed that the presence of an alkene group in the thioether side chain enhanced antifungal activity. Molecular docking studies with Pyricularia oryzae dihydroorotate dehydrogenase (PoDHODH) indicated that 3l forms a hydrogen bond with His89, while density functional theory (DFT) calculations provided insights into the electronic properties of the compounds. Additionally, ADMET predictions suggested that 3l has favorable pharmacokinetic properties, similar to the commercial fungicide tebufloquin. These findings highlight the potential of 3l as a lead compound for further development of novel antifungal agents.

Dapagliflozin in Chronic Kidney Disease: Insights from Network Pharmacology and Molecular Docking Simulation

Chronic kidney disease (CKD) involves inflammation, oxidative stress, and fibrosis, leading to renal dysfunction. Dapagliflozin, an SGLT2 inhibitor, shows renoprotective effects beyond glucose control, but its precise molecular mechanisms remain unclear. This study utilizes network pharmacology and molecular docking to elucidate its multi-target effects in CKD. Dapagliflozin’s SMILES structure was analyzed for ADMET properties. Potential targets were identified via SwissTargetPrediction, GeneCards, and SEA, and common CKD-related targets were determined. A protein–protein interaction (PPI) network was constructed, and key pathways were identified using GO and KEGG enrichment analyses. Molecular docking was conducted to validate dapagliflozin’s binding affinities with hub proteins. A total of 208 common targets were identified, including EGFR, GSK3β, and IL-6. GO and KEGG analyses highlighted key pathways, such as PI3K-Akt, MAPK, and AGE-RAGE, involved in inflammation, oxidative stress, and metabolic regulation. Molecular docking confirmed strong binding affinities with EGFR (−8.42 kcal/mol), GSK3β (−7.70 kcal/mol), and IL-6 (−6.83 kcal/mol). Dapagliflozin exhibits multi-target therapeutic potential in CKD by modulating inflammation, oxidative stress, and metabolic pathways. This integrative approach enhances the understanding of its mechanisms, supporting future experimental validation and clinical application in CKD management.

Comparison of PDE-5 inhibitors used in erectile dysfunction with some candidate molecules: A study involving molecular docking, ADMET, DFT, biological target, and activity

Erectile dysfunction (ED) is a urological condition defined as the inability of a man to achieve or maintain an erection. This condition negatively affects his sexual performance and the performance of his partner. Phosphodiesterase type 5 (PDE5) inhibitors are commonly used to treat ED. Arginase II plays an important role in regulating L-arginine to NO synthase in the smooth muscle of the human corpus cavernosum of the penis. NO is a molecule essential for regulating a variety of functions, including arterial blood pressure, penile erection, and energy balance. Substances such as vardenafil, alprostadil, papaverine, and resveratrol increase NO production, thereby supporting sexual function and vascular health. Additionally, NO donors such as L-arginine, L-citrulline, and α-lipoic acid provide effective alternatives when used in combination with PDE5 inhibitors. Medications used in the treatment of ED include vardenafil, alprostadil, and papaverine. In addition, although molecules such as L-arginine, citrulline, resveratrol, alpha-lipoic acid, and rutin are thought to play a role in ED, their pharmacological and molecular effects have not been sufficiently elucidated. The aim of this study was to investigate the effects of these molecules in the treatment of ED by computer-based calculations, to obtain new information about them and to inspire new treatment strategies for ED. The physicochemical, molecular and pharmacokinetic properties of the compounds were determined by SwissADME software, and ADMET (absorption, distribution, metabolism, excretion and toxicity) data were determined by ADMETlab 3.0 software. Biological target and activity data were obtained by MolPredictX and PASS Online software. While the Gaussian 09 program was used for DFT calculations, PyMOL, AutodockTools 4.2.6, AutoDock Vina, and Biovia Discovery programs were used for molecular docking studies. It was found that L-arginine, citrulline, resveratrol and α-lipoic acid were well absorbed from the intestine, while rutin showed limited absorption. When their metabolic risks were evaluated, L-arginine and citrulline were found to have lower toxicity. Molecular docking results of rutin and resveratrol were remarkable. The electronic properties of the compounds were explained by DFT calculations. L-arginine and citrulline were found to have low toxicity and positive therapeutic effects. L-arginine and citrulline stand out as promising candidates for future research. Although resveratrol data are promising, unfortunately their potential toxicity and metabolic interactions require further investigation. It is important to learn more about these compounds or conduct research to improve their therapeutic efficacy. Although computer-based calculations play an important role in toxicity predictions, drug interactions, pharmacokinetics and toxicity properties should be carefully evaluated.

Gengnianchun formula ameliorates insulin resistance-induced diminished ovarian reserve via the estrogen signaling pathway: evidence from network pharmacology and experimental validation

BackgroundDiminished ovarian reserve (DOR), a major cause of female infertility, is closely linked to insulin resistance (IR). Traditional Chinese Medicine (TCM) approaches, such as the Gengnianchun (GNC) formula, focus on restoring ovarian function by improving IR and regulating hormonal balance. Despite GNC’s demonstrated efficacy, its precise therapeutic mechanisms remain unclear.ObjectiveThis study aims to elucidate the mechanisms by which GNC ameliorates IR-induced DOR through comprehensive pharmacological and experimental validation.MethodsThe study combined Liquid chromatograph mass spectrometer (LC-MS), ultra-performance liquid chromatography (UPLC-TOF-MS/MS), network pharmacology, and molecular docking to identify active components and key therapeutic targets of GNC. Functional enrichment analyses (GO and KEGG) and molecular docking studies were performed. A high-fat diet-induced mouse model of IR-DOR was established, followed by GNC treatment at varying doses. Therapeutic effects were evaluated via qRT-PCR, western blot, immunofluorescence, and histological analysis.ResultsGNC contains 219 active ingredients targeting 53 genes associated with IR-induced DOR. KEGG analysis revealed the estrogen signaling pathway as a key mechanism. High-dose GNC significantly improved IR and ovarian reserve by increasing AKT1, ESR1, and ESR2 expression, as confirmed by qRT-PCR, western blot and immunofluorescence analysis. These findings indicate that GNC enhances insulin sensitivity, promotes follicular development, and restores ovarian function.ConclusionsThis study demonstrates for the first time that GNC alleviates IR-induced DOR by modulating the estrogen signaling pathway and activating key molecular targets. These results provide a foundation for clinical research and the development of novel therapeutic strategies for DOR.Clinical trial numberNot applicable

Camellia sinensis phytochemical profiling, drug-likeness, and antibacterial activity against gram-positive and gram-negative bacteria: in vitro and in silico insights

BackgroundCamellia sinensis extracts have a rich phytochemical profile and therapeutic properties. The plant contains bioactive compounds, such as catechins, flavonoids, and phenolic acids, which are associated with various health benefits, including antioxidant, anti-inflammatory, and anticancer activities.AimTo investigate the bioactive potential of a Camellia sinensis extract, particularly its antibacterial activity against Gram-positive and Gram-negative bacteria and its drug-like properties.MethodPhenolic compounds in C. sinensis extract were identified and quantified using high-performance liquid chromatography (HPLC). Its antibacterial activity was assessed against both Gram-positive (Staphylococcus aureus) and Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli). Drug-likeness, toxicity, and molecular properties of the identified compounds were investigated using computational approaches. Additionally, binding affinities of selected compounds were predicted via molecular docking to elucidate potential antibacterial mechanisms.ResultsHPLC identified caffeic acid (10.32 mg/g), epigallocatechin gallate (EGCG, 8.74 mg/g), syringic acid (6.21 mg/g), and quercetin (15.29 mg/g). Antibacterial activity testing revealed inhibition zones ranging from 10.62 mm for Gram-negative E. coli to 18.65 mm for Gram-positive S. aureus, comparable to gentamicin (19.42 mm). Molecular docking predicted that EGCG (−9.8 kcal/mol) was the most potent compound against Gram-negative P. aeruginosa RNase PH, followed by quercetin (−8.7 kcal/mol). Drug-likeness modeling indicated favorable profiles for most compounds, although EGCG violated Lipinski’s rule due to its molecular weight (458.4 g/mol). Density Functional Theory analysis revealed significant variations in electronic properties among the selected compounds, with quercetin exhibiting the smallest HOMO-LUMO gap (2.31 eV), suggesting high reactivity. MD simulations confirmed the stability of the EGCG-protein complex, with RMSD values (∼2.5–3.0 Å), reduced RMSF at key residues, and stable Rg (∼18–20 Å).DiscussionThe results highlight that C. sinensis is a valuable source of bioactive phenolic compounds with promising antibacterial properties against both Gram-positive and Gram-negative bacteria, particularly EGCG. Quercetin, the most abundant compound, showed better chemical stability (higher HOMO-LUMO gap), but its lower binding affinity suggests that EGCG is a more effective therapeutic candidate. Moreover, the antibacterial activity of these compounds positions them as potential alternatives to conventional antibiotics. Future research should focus on in vivo validation, structure-activity optimization, and formulation development to improve bioavailability and clinical applicability.

Derivatives of MOPS: promising scaffolds for SARS coronaviruses Macro domain-targeted inhibition.

The severe acute respiratory syndrome coronavirus (SARS-CoV/CoV-2) genome encodes 16 non-structural proteins (nsps), which coordinate cell remodeling, virus replication and participate in viral evasion. Notably, nsp3 contains a protein module termed Macro domain, which carries IFN antagonist activity that interferes with host innate immunity response. This domain is able to bind and hydrolyze ADP-ribose derivatives. This activity is correlated to viral escape and thus makes Macro domains a valuable therapeutic target. In the present paper, we report a SARS-CoV Macro domain structure in complex with a MOPS molecule. Based on our structural data, molecular docking was performed on a set of MOPS analogs in the ADP-ribose binding pocket. We present an ELISA-based assay to select hits based on the inhibition of recombinant SARS-CoV/CoV-2 Macro domain-ADP-ribose complex formation. Among the tested analogs, MOPSO and CAPSO are the more efficient in inhibiting ADP-ribose-binding. Structural analysis of these molecules in the ADP-ribose pocket reveals potential interactions with amino acid residues involved in the coordination of ADP-ribose. Overall, these findings suggest that MOPSO and CAPSO bear potential to be used as a scaffold for the design of Macro domain-specific inhibitors.

A Novel Missense Mutation at EDA2R Gene Identified in a Case Study Associated with Hypohidrotic Ectodermal Dysplasia

Article A Novel Missense Mutation at EDA2R Gene Identified in a Case Study Associated with Hypohidrotic Ectodermal Dysplasia Wan Yang 1,†, Siyu Jin 1,†, Jie Jiang 1, Wei Ji 1,2,*,‡ and Qing He 1,*,‡ 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430000, China 2 Department of Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan 430000, China * Correspondence: wei.ji@whu.edu.cn (W.J.); qing.he@whu.edu.cn (Q.H.); Tel.: +86-131-0061-5376 (W.J.); +86-183-2719-2492 (Q.H.) † These authors contributed equally as first authors. ‡ These authors share equal senior authorships. Received: 3 January 2025; Revised: 11 February 2025; Accepted: 25 February 2025; Published: 11 March 2025 Abstract: Hypohidrotic Ectodermal Dysplasia (HED) is a rare genetic disorder characterized by hypodontia, hypohidrosis, and hypotrichosis. The study aims to identify a novel mutation in the EDA2R gene in a 20-year-old female with HED and investigate its impact on the NF-κB signaling pathway. Whole genome sequencing confirmed the mutation, and bioinformatic tools predicted it to be pathogenic by destabilizing the EDA2R structure and weakening its interaction with EDA-A2. Molecular dynamics simulation and binding free energy calculations further revealed reduced hydrogen bond formation in the mutant EDA2R/EDA-A2 complex, while molecular docking and AlphaFold analyses indicated decreased binding to TRAF3 and TRAF6. In vitro experiments demonstrated that cells expressing the mutant EDA2R had significantly reduced proliferation and NF-κB activity, along with impaired nuclear translocation of NF-κB p65. However, Western blot analysis showed that the JNK signaling pathway remained unaffected. This study identifies a novel missense mutation in EDA2R and introduces a new pathogenic mechanism of HED, emphasizing the crucial role of EDA2R in regulating NF-κB signaling.

7-(4-Chlorophenyl)-1-hydroxy-5-methylpyrido[3,4-d]pyridazin-4(3H)-one: synthesis, solvatomorphism, in vitro anti-inflammatory and cytotoxic activity studies and in silico analysis.

The newly obtained compound 7-(4-chlorophenyl)-1-hydroxy-5-methylpyrido[3,4-d]pyridazin-4(3H)-one (CPM) was crystallized as two new variable solvates, namely, the dimethyl sulfoxide monosolvate, C14H10ClN3O2·C2H6SO (I), and the sesquisolvate, C14H10ClN3O2·1.5C2H6SO (II), and their structures were confirmed by single-crystal X-ray diffraction analysis. In previous work, 1-hydroxy-5-methyl-7-phenylpyrido[3,4-d]pyridazin-4(3H)-one (PM) was found to display anticancer activity. In the next step of our studies, we synthesized a new derivative of PM, introducing a Cl atom into the PM structure, obtaining CPM, which showed not only anticancer but also anti-inflammatory activity. CPM and the new semi-products of each step of the synthesis were examined by 1H NMR, 13C NMR and FT-IR spectroscopic analyses, and mass spectrometry. CPM forms (I) and (II) crystallize in the triclinic P1 and monoclinic C2/c space groups, respectively, and differ in the stoichiometry of the CPM and DMSO molecules in the crystal lattice, being 1:1 and 1:1.5 for (I) and (II), respectively. A powder X-ray diffraction analysis was performed only for solvate (I) due to the lack of stability of solvate (II). The potential cytotoxicity of CPM was evaluated against the normal cell lines L929 and RPTEC, as well as the cancer cell lines A172, AGS, CACO-2 and HepG2. The anti-inflammatory activity of CPM was also evaluated using colorimetric assay for the inhibition of COX-1 and COX-2. The same biological tests were carried out for PM to compare the activities of both compounds. The biological studies revealed that CPM does not exhibit more activity than PM. Moreover, in silico analysis of the bioavailability and molecular docking were performed.

EXPRESS: In Silico Exploration of Bioactive Secondary Metabolites with Anesthetic Effects on Sodium Channels Nav 1.7, 1.8, and 1.9 in Painful Human Dental Pulp.

To investigate the efficacy of medicinal plant bioactive secondary metabolites as inhibitors of voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) in managing painful states of dental pulps. Molecular docking, ADME prediction, toxicity profiling, and pharmacophore modelling were used to assess the binding affinities, pharmacokinetic properties, toxicological profiles, and active pharmacophores of the selected bioactive compounds. Three compounds (Sepaconitine, Lappaconitine and Ranaconitine) showed binding affinities (ΔG = -8.95 kcal/mol, -7.77 kcal/mol and -7.44 kcal/mol, respectively) with all three Nav1.7, Nav1.8 and Nav1.9 sodium channels. The sepaconitine amine group formed hydrophobic interactions with key residues. The Lappaconitine benzene ring contributed to hydrophobic interactions and hydrogen bond acceptor interactions. The hydrophobic interactions of the ranaconitine amine group play a critical role with specific residues on Nav1.8 and Nav1.9. The natural fusicoccane diterpenoid derivatives Sepaconitine, Lappaconitine, and Ranaconitine are potential lead compounds for the development of novel analgesics as selective antihyperalgesic drugs, which will provide a new dental pharmacological intervention for managing painful dental pulp conditions. Further experimental validation and clinical studies that confirm the efficacy and safety of these compounds will strengthen their applicability in dental practice.

Efficient Synthesis, Anticancer Evaluation of Triazole-Thiadiazole/Benzo[d]Oxazole Scaffolds, and Investigation of Their Reactivity Properties Using Density-Functional Theory Calculations and In Silico Docking.

The present study describes a benzo[d]oxazole-functionalized conventional synthesis of novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles are formed by the condensation of 5 with bromo-substituted acetophenones and isothiocyanates. The structural elucidation of the newly synthesized compounds was accomplished using various spectroscopic techniques, for example, Fourier transform infrared, nuclear magnetic resonance (1H/13C), and high-resolution mass spectrometry. We examined all the newly synthesized compounds for their in vitro anticancer potential against breast cancer cell lines. As the most prominent one, compound 6c showed the highest anticancer activity against the MDA-MB-231 cell line and a half-maximal inhibitory concentration (IC50) value of 3.01 ± 0.45µM, which was close to that of the positive control Doxorubicin (IC50 value of 3.10 ± 0.27µM). It was also observed that compound 8e (IC50 = 3.92 ± 0.04µM) exhibited superior activity against the T47D cell line, whereas compound 6f (IC50 = 2.10 ± 0.21µM) demonstrated better activity against the MCF-7 cell line. In silico docking investigations of the representative ligands further explored the characteristic binding orientations on conserved interactions with residues like LysA:55, ValA:60, ThrA:11, GluA:14, ProA:57, AlaA:15, SerA:51, and GlyA:58 from the breast cancer estrogen receptor beta enzyme (PDB code: 1U9E). We utilized density-functional theory (DFT) analyses to deduce the molecular structures and topologies of the more energetic molecules. Furthermore, the positive absorption, distribution, metabolism, excretion, and toxicity properties of these derivatives highlight their potential as therapeutics, calling for more research into possible clinical applications. The tested compounds' structure-activity relationships are in good agreement with molecular docking and DFT studies, which demonstrate that the primary cause of the high anticancer activity of 1,2,4-triazole hybrids is the presence of a lipophilic and heterocyclic substituent on the benzo[d]oxazole component.

Quantum Chemical and Metabolomic Characterization of Inhibitory Activity of Procyanidins and Flavonol Glucosides from Graptopetalum paraguayense E. Walther against Nonstructural Proteins of SARS-CoV-2.

This study explores the antiviral potential of Graptopetalum paraguayense (GP) against SARS-CoV-2 nonstructural proteins (NSPs). GP, a plant known for its health benefits, has previously shown strong antiviral activity against HSV-1, and although the two viruses have different taxonomy, its effectiveness against the new coronavirus was also examined. LC-ESI-QTOF-MS/MS analysis identified fourteen polyphenolic metabolites in GP, including procyanidins and flavonol glucosides, compounds associated with anti-coronavirus properties. These compounds were tested using molecular docking and ONIOM(B3LYP/6-31+G(d,p):UFF) quantum chemical calculations to assess their binding affinity to eight SARS-CoV-2 NSPs critical for viral replication and transcription. The results revealed that GP compounds, such as procyanidin B2, kaempferol-3-O-glucoside, and epicatechin-3-O-galactoside, had strong binding affinities to NSP14, NSP5, and NSP15, respectively, suggesting their potential to inhibit viral replication. Compared to known NSP inhibitors from the RCSB Protein Data Bank, GP-derived compounds demonstrated comparable or superior interaction energies in several cases. This investigation highlights GP's therapeutic potential as a natural antiviral against SARS-CoV-2. The findings provide new insights into the role of plant-derived polyphenols in targeting viral proteins and contribute to further experimental and clinical studies to validate these compounds as candidates for anti-coronavirus therapies.

Robust Acid-Responsive AILE Luminescence Effect Nanoparticle for Drug Release Monitoring and Induction of Apoptosis in Cancer Cells.

Through the PFOEP-SO3(-) + multidrug molecules constructed nanoparticle (NP) experiments and validated by molecular simulation docking experiments, we propose a molecular interaction principle for inducing aggregation-induced locally excited emission (AILE) luminescence from fluorenone (FO)-based conjugated polymers (CPs). Based on this molecular interaction mechanism, we constructed a NP built by π-π stacking. The NPs demonstrate facile synthesis, robust stability, and high drug-loading efficiency, enabling tumor-specific drug release in acidic lysosomal environments (pH 3.8-4.7) to minimize off-target toxicity. Concurrently, the PFOEPA NPs exhibit pH-dependent fluorescence enhancement: drug incorporation induces structural reorganization into a "sandwich" configuration, amplifying fluorescence with a blue shift under neutral/alkaline conditions, while acidic-triggered protonation collapse disrupts NPs. Moreover, it can be used as an indicator for monitoring drug release, as it is accompanied by changes in fluorescence during the drug release process. This NP possesses multiple functions and is expected to serve as an effective pH-responsive drug delivery system.

Molecular modelling and docking of cloned pectin lyases from Fusarium species

Molecular modelling and docking of cloned pectin lyases from Fusarium species

The Membrane-Targeting Synergistic Antifungal Effects of Walnut-Derived Peptide and Salicylic Acid on Prickly Pear Spoilage Fungus

Fermented walnut (FW) meal exhibits antifungal activity against Penicillium victoriae (the fungus responsible for prickly pear spoilage), which is mainly attributed to the synergistic effect of antimicrobial peptides and salicylic acid (SA). This study aimed to investigate the synergistic mechanism between YVVPW (YW-5, the peptide with the highest antifungal activity) and SA against the cell membrane of P. victoriae. Treatment enhanced prickly pear’s rot rate, polyphenol concentration, and superoxide dismutase (SOD) activity by 38.11%, 8.11%, and 48.53%, respectively, while reducing the microbial count by 19.17%. Structural analyses revealed β-sheets as YW-5′s predominant structure (41.18%), which increased to 49.0% during SA interaction. Molecular docking demonstrated YW-5′s stronger binding to β-(1,3)-glucan synthase and membrane protein amino acids via hydrogen bonds, hydrophobic forces, and π-π conjugate interactions. Spectroscopic analyses demonstrated SA’s major role in YW-5 synergy at the interface and polar head region of phospholipids, enhancing lipid chain disorder and the leakage of cell components. Malondialdehyde and SOD levels increased nearly two-fold and six-fold when treated with YW-5/SA, and YW-5 showed a more pronounced effect. Scanning electron and transmission electron microscopy confirmed that SA caused greater damage to spore morphology and cell ultrastructure. These findings support this formulation’s functions as an efficient antifungal substance in fruit storage.

Green Synthesis of Silver Nanoparticles: Enhancing Cisplatin Binding to Biomolecules for Improved Drug Delivery and Therapeutic Synergy.

Cisplatin and other anticancer drugs face challenges such as systemic toxicity and drug resistance, necessitating novel delivery strategies. Nanoparticles have revolutionized drug delivery by enhancing the efficacy and bioavailability of therapeutic agents. In this study, silver nanoparticles (AgNPs) were green-synthesized using Chromolaena odorata (CO) and characterized using UV-Vis spectroscopy, Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDS), x-ray diffraction (XRD), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). The interactions of Co-AgNPs, cisplatin, and their combination with biomolecules calf thymus DNA (ctDNA), bovine serum albumin (BSA), and human serum albumin (HSA) were assessed for complex formation and structural alterations in the biomolecules. UV-Vis spectroscopy revealed surface plasmon resonance at 441 nm. SEM analysis indicated a near-Gaussian size distribution with a mean diameter of 0.44 μm, while TEM confirmed the predominantly spherical morphology and polydispersity of the AgNPs within a size range of 10.5-32.9 nm. XRD confirmed a face-centered cubic (FCC) crystalline structure with an average size of 15.57 nm, and EDS indicated the presence of silver, chlorine, oxygen, and nitrogen in the nanoparticle composition. TGA demonstrated the thermal stability of the nanoparticles up to 220°C. Bioassay experiments showed that AgNPs and cisplatin individually interacted with ct-DNA to form stable complexes; the combined AgNP-cisplatin system induced significant conformational changes in the DNA structure, indicating a synergistic effect. Similarly, BSA binding studies revealed stable complex formation with both AgNPs and the AgNP-cisplatin combination, causing pronounced conformational changes in the protein. For HSA, the combination exhibited enhanced binding efficiency compared to individual agents, suggesting improved transport and bioavailability potential. Moreover, molecular docking studies demonstrated that the combined AgNP-cisplatin system exhibited the lowest Etotal of -254 kcal/mol, compared to -223.35 kcal/mol for AgNPs and -112.30 kcal/mol for cisplatin alone. This indicates that the combined system interacts more strongly with ct-DNA, likely within the minor groove, displaying enhanced binding affinity.