Docking Experiments Research Articles

Predictive Analysis of Yi-Gai-San's Multifaceted Mechanisms for Tremor-dominant Parkinson's Disease via Network Pharmacology and Molecular Docking Validation.

Based on comprehensive network-pharmacology and molecular docking analysis, this study was intended to unveil the multiple mechanisms of Yi- Gai-San (YGS) in treating the tremor-dominant subtype of Parkinson's disease (PD-DT). The compounds of YGS were meticulously analyzed, selected, and standardized with references to their pharmacological attributes. Its components included Gouteng (Uncaria rhynchophylla), Chaihu (Radix Bupleuri), Chuanxiong (Chuanxiong Rhizoma), Danggui (Angelicae sinensis radix), Fuling (Wolfiporia extensa), Baizhu (Atractylodis macrocephalae rhizoma), and Gancao (Licorice, Glycyrrhizae radix). We identified 75 active compounds within YGS. From these, we predicted 110 gene targets, which exhibited a direct association with PD-DT. PPI network results highlighted core target proteins, including TP53, SLC6A3, GAPDH, MAOB, AKT, BAX, IL6, BCL2, PKA, and CASP3. These proteins potentially alleviate PD-DT by targeting inflammation, modulating neuronal cell apoptosis, and regulating the dopamine system. Furthermore, GO and KEGG enrichment analyses emphasized that YGS might influence various mechanisms, such as the apoptotic process, mitochondrial autophagy, Age-Rage signaling, and dopaminergic and serotonergic synapses. The core proteins from the PPI analysis were selected for the docking experiment. The docking results demonstrated that the most stable ligand-receptor conformations were kaempferol with CASP3 (-9.5 kcal/mol), stigmasterol with SLC6A3 (-10.5 kcal/mol), shinpterocarpin with BCL2L1 (-9.6 kcal/mol), hirsutine with MAOB (-9.7 kcal/mol), hederagenin with PRKACA (-9.8 kcal/mol), and yatein with GAPDH (-9.8 kcal/mol). These results provide us with research objectives for future endeavors in extracting single compounds for drug manufacturing or in-depth studies on drug mechanisms. From these computational findings, we suggested that YGS might mitigate PD-DT via "multi-compounds, multi-targets, and multi-pathways."

Synthesis, Crystal Structure, Spectroscopic Characterization, In Vitro and In Silico Molecular Docking Studies of Benzyl Tetrazole-N-Isobutyl Acetamide Hybrid

Background: Tetrazole-based compounds are of significant interest due to their potential pharmacological applications. The current study focuses on the synthesis and analysis of such a compound. Objective: This research aims to synthesize the title compound N-(3-methyl-1-phenyl-2-(1Htetrazol- 1-yl) butyl) acetamide, analyze its crystal structure, perform computational studies, and evaluate its potential pharmacological activities and it’s in silico and in vitro supports, specifically antidiabetic and anti-inflammatory properties. Methods: The title compound, C14H19N5O, was synthesized, and its crystal structure was confirmed using single-crystal X-ray diffraction analysis by default parameters. Density Functional Theory (DFT) calculations were performed using the Gaussian 09W software package with the B3LYP/6-311++G (d,p) method to optimize the compound's structure and calculate its HOMOLUMO energy gap, Molecular Electrostatic Potential (MEP), and Mulliken charge distribution. In vitro, antidiabetic and anti-inflammatory activities were assessed and compared with standard drugs by using reported protocols. Additionally, molecular docking studies were conducted with enzymes related to diabetes and inflammation with default parameters, and Auto-Dock 4.2 software was used. Results: The X-ray diffraction analysis confirmed the crystal structure, and the Density Functional Theory (DFT) calculations provided insights into the molecular properties of the compound. Molecular docking experiments with relevant enzymes further supported the significant antidiabetic and anti-inflammatory activities demonstrated in the in vitro tests. Conclusion: The synthesized tetrazole-based compound exhibits promising antidiabetic and antiinflammatory activities, supported by both experimental and theoretical studies, suggesting its potential for further pharmacological investigation.

Synthesis, Characterization, Density Functional Theory Study, Antibacterial Activity and Molecular Docking of Zeolitic Imidazolate Framework‐8

ABSTRACTIn this study, Zeolitic Imidazolate Framework‐8 (ZIF‐8) nanomaterials were synthesized using a co‐precipitation one‐pot method that uses ethanol, methanol, and water as solvents for the precursors (2‐methylimidazole and Zinc nitrate hexahydrate), resulting in yields of 66.77%, 73.14%, and 68.12%, respectively. The as‐synthesized ZIF‐8 nanomaterials were thoroughly characterized by X‐ray diffraction analysis, transmission electron microscopy, ultraviolet–visible spectroscopy, and Fourier‐transform infrared spectroscopy. The X‐ray diffraction analysis showed that the crystallite size of ethanol‐based ZIF‐8 (24.76 ± 1.67 nm) was smaller than those synthesized in water (26.92 ± 1.89 nm) and methanol (31.39 ± 1.03 nm). However, methanol‐based ZIF‐8 exhibited lower crystallinity (85.93%) than water‐based ZIF‐8 (91.48%) and ethanol‐based ZIF‐8 (92.71%). Zeta potential studies revealed that ethanol‐based ZIF‐8 had a larger surface charge (+37 mV) than water‐based ZIF‐8 (+35 mV) or methanol‐based ZIF‐8 (+24 mV). Transmission electron microscopy analysis confirmed particle sizes of 54.35 ± 2.11 nm for ethanol‐based ZIF‐8, 57.91 ± 2.26 nm for water‐based ZIF‐8, and 63.25 ± 4.12 nm for methanol‐based ZIF‐8. Thermogravimetric analysis indicated thermal stability up to 800 °C, with mass losses of 55.98% for ethanol‐ZIF‐8, 50.12% for water‐based ZIF‐8, and 65.36% for methanol‐based ZIF‐8 by 600 °C. In antibacterial studies, water‐based ZIF‐8 exhibited the largest zone of growth inhibition (17.30 ± 0.26 mm) against Escherichia coli compared to ethanol‐based ZIF‐8 (15.57 ± 0.32 mm) and methanol‐based ZIF‐8 (14.70 ± 0.20 mm). Pearson's correlation study revealed that zeta potential, crystallinity, and antibacterial activity are positively related. Furthermore, water‐based ZIF‐8, with a minimum inhibitory concentration of 50 μg/100 μL, confirmed evident cell membrane disruption. Molecular docking experiments revealed ZIF‐8's significant binding affinity for the E. coli protein 5AZC, supporting its robust antibacterial activity.

Mechanism of Asperosaponin VI Related to EGFR/MMP9/AKT/PI3K Pathway in Treatment of Rheumtoid Arthritis.

To explore the mechanism of action of asperosaponin VI (AVI) in the treatment of rheumatoid arthritis (RA) and validate it in ex vivo experiments using network pharmacology and molecular docking methods. The predicted targets of AVI were obtained from PharmMaper, UniProt and SwissTarget Prediction platforms, the disease targets were collected from Online Mendelian Inheritance in Man, Therapeutic Target Database and GeneCards databases, the intersection targets of AVI and RA were obtained from Venny 2.1.0, and the protein-protein interaction (PPI) network was obtained from STRING database, which was analyzed by Cytoscape software and screened to obtain the core targets. Cytoscape software was used to analyze PPI network and screen the core targets. Based on the Database for Annotation, Visualization and Integrated Discovery database, Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed, and Cytoscape software was used to construct the "Disease-Pathway-Target-Drug" network, which was finally verified by molecular docking and animal experiments. Network pharmacological studies showed that AVI was able to modulate 289 targets, with 102 targets for the potential treatment of RA, with the core pathway being the AKT/PI3K signaling pathway, and the core targets being the epidermal growth factor receptor (EGFR) and matrix metalloproteinase 9 (MMP9). Molecular docking results showed that AVI could produce strong binding with both of the 2 core targets. In vitro cellular experiments showed that AVI reduced nitric oxide, prostaglandin E2, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 β levels (P<0.05) and inhibited cyclooxygenase-2, nitric oxide synthase, EGFR, MMP9, phosphorylated phosphoinositide 3-kinase (p-PI3K), and phosphorylated serine-threonine kinase (p-AKT) proteins (P<0.05). The results of in vivo studies showed that AVI improved RA score and foot swelling thickness and decreased TNF-α, IL-6, p-PI3K and p-AKT levels in RA rats (P<0.05). AVI exerts anti-inflammatory and anti-RA effects which might be related to the EGFR/MMP9/AKT/PI3K pathway.

YTHDC1 is a therapeutic target for B-cell acute lymphoblastic leukemia by attenuating DNA damage response through the KMT2C-H3K4me1/me3 epigenetic axis.

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive malignancy characterized by the aberrant accumulation of immature and dysfunctional B cells in bone marrow (BM). Although chemotherapy and other therapies have been widely applied, some patients such as relapsed ordrug-refractory (R/R) B-ALL patients exhibit limited response. YT521-B homologous domain-containing protein 1 (YTHDC1) is a nuclear reader of N6-methyladenosine (m6A) RNA modification, which has been implicated in different malignancies including leukemia. In the current study, we show that YTHDC1 is highly expressed in B-ALL cells. YTHDC1 knockdown attenuated B-ALL cell proliferation and cell cycle progression in vitro, and prolonged survival of mice in the human B-ALL xenograft model in vivo attributable to compromised leukemogenesis. Mechanistically, YTHDC1 knockdown significantly increased the accumulation of endogenous and chemotherapeutic agents-induced DNA damage in B-ALL cells. Furthermore, we identified that YTHDC1 binds to and stabilizes m6A-modified KMT2C mRNA. KMT2C is a key enzyme catalyzing histone H3K4 methylation required for the expression of DNA damage response (DDR)-related genes, implying that YTHDC1 inhibitors might improve chemotherapy by attenuating DDR via reducing KMT2C. Indeed, with molecular docking and biochemical experiments, we identified EPZ-5676 as a YTHDC1 inhibitor, and combination of EPZ-5676 with Cytarabine (Ara-c) significantly improved the efficacy of chemotherapy in B-ALL mouse models using YTHDC1high primary and lined B-ALL cells. Collectively, YTHDC1 is required for DDR in B-ALL cells by upregulating DDR-related gene expression via stabilizing m6A-modified KMT2C mRNA, thereby leading to increased histone H3K4 methylation, and targeted inhibition of YTHDC1 is a potentially new therapeutic strategy against B-ALL, especially YTHDC1high B-ALL.

Screening for Potential Antiviral Compounds from Cyanobacterial Secondary Metabolites Using Machine Learning

The secondary metabolites of seawater and freshwater blue-green algae are a rich natural product pool containing diverse compounds with various functions, including antiviral compounds; however, high-efficiency methods to screen such compounds are lacking. Advanced virtual screening techniques can significantly reduce the time and cost of novel antiviral drug identification. In this study, we used a cyanobacterial secondary metabolite library as an example and trained three models to identify compounds with potential antiviral activity using a machine learning method based on message-passing neural networks. Using this method, 364 potential antiviral compounds were screened from &gt;2000 cyanobacterial secondary metabolites, with amides predominating (area under the receiver operating characteristic curve value: 0.98). To verify the actual effectiveness of the candidate antiviral compounds, HIV virus reverse transcriptase (HIV-1 RT) was selected as a target to evaluate their antiviral potential. Molecular docking experiments demonstrated that candidate compounds, including kororamide, mollamide E, nostopeptolide A3, anachelin-H, and kasumigamide, produced relatively robust non-covalent bonding interactions with the RNase H active site on HIV-1 RT, supporting the effectiveness of the proposed screening model. Our data demonstrate that artificial intelligence-based screening methods are effective tools for mining potential antiviral compounds, which can facilitate the exploration of various natural product libraries.

Integrated strategy of mass spectrometry imaging and LC/MS-based GNPS for spatial characterization of alkaloids from Menispermi Rhizoma and study on potential anti-inflammatory mechanism by network pharmacology and molecular docking

Menispermi Rhizoma (MR) is the dried rhizome of Menispermum dauricum DC, which has been used to treat sore throat, enteritis, and rheumatic arthralgia. These therapeutic effects are attributed to its alkaloid ingredient. However, the chemical composition, anti-inflammatory mechanisms and the spatiotemporal distribution of the bioactive ingredients in MR have seldom been investigated. This study aims to clarify the anti-inflammation mechanism, material basis, and their spatial distribution of MR. Here, a LC/MS-based Global Natural Products Social Molecular Networking (GNPS) strategy was used to rapidly exhibit alkaloid molecular clusters that improve annotation accuracy and discover more unknown compounds. Then, a high-sensitive air flow-assisted ionization mass spectrometry imaging (AFAI-MSI) method was developed to visualize the spatial distributions alkaloids in different botanical parts of MR. The anti-inflammation mechanism was investigated based on network pharmacology and verified by molecular docking experiment. Finally, a total of 106 alkaloids including 24 aporphines, 23 monobenzylisoquinolines, 20 morphinanes, 20 proberberines, 12 bisbenzylisoquinolines, and 7 amides were identified in MR as well as 24 alkaloids were visualized in the medullary ray, cortex and epidermis regions. Moreover, the targets with a higher degree in the PPI network were TNF, GAPDH, AKT1, ALB, STAT3. GO and KEGG analysis revealed that MR in anti-inflammatory mechanism mainly involved plasma membrane, ATP binding, cytoplasm, identical protein binding and ATP binding. The signaling pathways mainly included NOD-like receptor signaling pathway, PI3K-Akt signaling pathway, AGE-RAGE signaling pathway in diabetic complications. The molecular docking results indicated that stepharanine-2-O-glucoside, bianfugedine, bianfugecine, dehydrostephanine had excellent affinity with SRC, MMP9 AKT1, STAT3 and TNF. This study comprehensively characterized the alkaloid ingredients and spatial distribution of MR, and revealed potential mechanism of MR in inflammation, which provides a reference for development and application of MR and other Traditional Chinese medicines (TCMs).

Identification of highly conserved surface-exposed peptides of spike protein for multiepitope vaccine design against emerging omicron variants: An immunoinformatic approach

The COVID-19 pandemic, originating in Wuhan in 2019, was caused by SARS-CoV-2, leading to significant global fatalities. Despite the development of vaccines, the virus mutates, creating variants that evade vaccine-induced immunity. To address SARS-CoV-2′s evolving nature, a multiepitope vaccine was developed using immunoinformatics approach, specifically targeting the Omicron variant’s spike protein. This vaccine includes six CD8 + and eleven CD4 + epitopes selected for their immunogenicity, non-toxicity, and significant conservation among former Variants of Concern (VOCs) and Variants of Interest (VOIs), such as Alpha, Beta, Gamma, Delta, Lambda, Mu, R1, and Zeta, as well as current Variants Under Monitoring (VUMs) like XBB.1.5, XBB.1.16, EG.5, BA.2.86, and JN.1. Notably, certain epitopes like ELLHAPATV and PYRVVVLSFELLHAP were fully conserved across all tested variants in the spike protein’s receptor binding domain (RBD). Others, such as NATRFASVYAWNRKR, were fully conserved in all former VOCs and VOIs and 93.33 % in current VUMs, while ERDISTEIYQAGNKP was entirely conserved in current VUMs within the RBD region. The study went on to model, refine, and validate the vaccine prototype’s tertiary structure. Docking experiments and molecular dynamic simulations revealed robust and stable interactions with Toll-like receptor 4. Cloning and codon optimization confirmed successful expression in E. coli. Subsequently, the immunological reaction of the multiepitope vaccine demonstrated that the three-time administration of the prototype significantly enhanced the antibody response while decreasing the number of antigens. The designed vaccine’s epitopes showed significant combined global population coverage of 100 % with 89.75 % for CD8 + and 99.98 % for CD4 + epitopes and conservation across SARS-CoV-2 variants especially in current monitoring omicron subvariants, supporting its broader applicability and potential efficacy. Although, this promising vaccine candidate needs to undergo clinical trials to determine its effectiveness in neutralising SARS-CoV-2.

Developing a chimeric multiepitope vaccine against Nipah virus (NiV) through immunoinformatics, molecular docking and dynamic simulation approaches

Nipah virus (NiV) is a highly lethal zoonotic pathogen that poses a significant threat to human and animal health. Unfortunately, no effective treatments have been developed for this deadly zoonotic disease. Therefore, we designed a chimeric multiepitope vaccine targeting the Nipah virus (NiV) glycoprotein and fusion protein through immunoinformatic approaches. Therefore, the vaccine was developed by combining promising and potential antigenic MHC-I, MHC-II, and B-cell epitopes obtained from the selected proteins. When combined, the MHC-I and MHC-II epitopes offered 100% global population coverage. The physicochemical characterization also exhibited favorable properties, including solubility and potential functional stability of the vaccine within the body (GRAVY score of -0.308). Structural analyses unveiled a well-stabilized secondary and tertiary structure with a Ramachandran score of 84.4% and a Z score of -5.02. Findings from docking experiments with TLR-2 (-1089.3 KJ/mol) and TLR-4 (-1016.7 KJ/mol) showed a strong affinity of the vaccine towards the receptor. Molecular dynamics simulations revealed unique conformational dynamics among the "vaccine-apo," "vaccine-TLR-2," and "vaccine-TLR-4" complexes. Consequently, the complexes exhibited significant compactness, flexibility, and exposure to solvents. The results of the codon optimization were remarkable, as the vaccine showed a significant amount of expression in the E. coli vector (GC content of 45.36 % and a CAI score of 1.0). The results of immune simulations, however, showed evidence of both adaptive and innate immune responses induced by the vaccine. Therefore, we highly recommend further research on this chimeric multiepitope vaccine to establish its efficacy and safety against the Nipah virus (NiV).

Network Pharmacology and Molecular Docking Analysis on Mechanisms of Scutellariae Radix in the Treatment of Cerebral Ischemia-reperfusion Injury.

Multiple brain disorders are treated by Scutellaria Radix (SR), including cerebral ischemia-reperfusion (CI/R). However, more studies are needed to clarify the molecular mechanism of SR for CI/R. The active substances and potential targets of SR and CI/R-related genes were obtained through public databases. Overlapping targets of SR and CI/R were analyzed using proteinprotein interaction (PPI) networks. GO and KEGG enrichment analyses were performed to predict the pathways of SR against CI/R, and the key components and targets were screened for molecular docking. The results of network pharmacology analysis were verified using in vitro experiments. 15 components and 64 overlapping targets related to SR and CI/R were obtained. The top targets were AKT1, IL-6, CAS3, TNF, and TP53. These targets have been studied by GO and KEGG to be connected to a number of signaling pathways, including MAPK, PI3K-Akt pathway, and apoptosis. Molecular docking and cell experiments helped to further substantiate the network pharmacology results. The active compound of SR was able to significantly decrease the apoptosis of HT- 22 cells induced by OGD/R. This finding suggests that SR is a potentially effective treatment for CI/R by modulating the MAPK and PI3K-Akt pathways.

In silico exploration of phytocompounds from AYUSH-64 medicinal plants against SARS CoV-2 RNA-dependent RNA polymerase

BackgroundThe AYUSH 64 formulation helps to treat mild to moderate cases of COVID-19. Although several drugs have been proposed to combat COVID-19, no medication is available for SARS-CoV-2 infection. The RNA-dependent RNA polymerase (RdRp) is the pivotal enzyme of SARS-CoV-2 replication, so it could be considered a better drug target for experimental studies. ObjectiveThe AYUSH-64 formulation plants exhibited multiple therapeutic properties; thus, the present study aims to screen the phytocompounds of these plants against SARS CoV2 RdRp to identify specific compounds that could potentially affect COVID-19 infection. Materials and methodsPatchDock and AutoDock tools were used for docking experiments. MD simulations and Density Functional Theory (DFT) calculations of protein-ligand Picroside-I and Remdesivir complexes were carried out in GROMACS v2019.4 and Gaussian 09 software, respectively. ResultsAmong the tested, five phytocompounds (Picroside I, Oleanolic acid, Arvenin I, II, and III) from AYUSH-64 medicinal plants showed possible binding with RdRp catalytic residues (Ser759, Asp760, and Asp761). Of these, Picroside I exhibited hydrogen bond interactions with NTP entry channel residues (Arg553 and Arg555). The MM-PBSA free energy, RMSD, Rg, PCA, and RMSF analysis suggested that the Picroside I complex showed stable binding interactions with RdRp in the 50 ns simulation. In addition to this, Picroside I revealed its robust and attractive nature toward the target protein, as confirmed by DFT. ConclusionThe results of this study have proposed that Picroside I from AYUSH 64 medicinal plant compounds was the selective binder of catalytic and NTP entry channel residues of SARS-CoV2 RdRp thereby; it may considered as a potential inhibitor of SARS-CoV2 RdRp.

Ergotamine Targets KIF5A to Facilitate Anoikis in Lung Adenocarcinoma

ABSTRACTBackgroundKinesin family member 5A (KIF5A) has been reported to be closely related to cancer progression. The aim of this study was to investigate the effect of KIF5A on lung adenocarcinoma (LUAD) and its potential molecular mechanisms.MethodsUsing bioinformatics analysis methods and molecular experiments, the expression of KIF5A in LUAD was analyzed, with its expression in attached and detached tumor cells assessed. Gene set enrichment analysis (GSEA) of KIF5A was carried out. The small molecular drug with the highest affinity for KIF5A was screened out through molecular docking experiments, which was validated through cellular thermal shift assay (CETSA). Quantitative polymerase chain reaction (qPCR) was employed to measure the expression levels of anoikis‐repressing genes (BCL2, CAV1), as well as anoikis‐inducing gene (PDCD4). CCK‐8 assay was applied to examine cell viability. Cell colony formation experiments were utilized to evaluate cell proliferation ability.ResultsWe observed that KIF5A was highly upregulated in LUAD tissues and cells, with a higher level detected in detached LUAD cells. By resorting to bioinformatics analysis, we discovered that KIF5A was abundant in the anoikis pathway. Knocking down KIF5A reinforced anoikis in LUAD. Further screening identified Ergotamine as the small molecular drug with the highest affinity for KIF5A. The CETSA confirmed the binding relationship between the two. In addition, Ergotamine has a promoting effect on the anoikis of LUAD, while overexpression of KIF5A reversed the effects of Ergotamine on LUAD cells.ConclusionThis project uncovered that the small molecular drug Ergotamine targets and inhibits the expression of KIF5A. Downregulated KIF5A can enhance the anoikis of LUAD. Our results supported the inhibition of KIF5A as an attractive therapeutic strategy for LUAD. This finding provides a new innovative pathway for the treatment of LUAD and offers a strong theoretical basis for the development of therapeutic drugs targeting KIF5A.

Design, Synthesis, and Hypoxia-Inducible Factor-1α Inhibitory Activity Evaluation of Panaxadiol Derivatives Containing a Thiazole Moiety.

The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Thiazole derivatives have been reported to have diverse biological activities, especially in terms of anti-tumor. Consequently, we hypothesized that the introduction of a thiazole functional group in PD was likely to improve the biological potency. Here, three series of PD derivatives containing a thiazole moiety were synthesized, including (a) sulfonyl-containing thiazole derivatives (5 a-l), (b) urea-containing thiazole derivatives (7 a-i), and (c) thiourea-containing thiazole derivatives (9 a-i), and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. The results showed that about 1/3 of the target compounds showed moderate or strong HIF-1α inhibitory activity, among which compounds 5 d and 7 b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 μM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50 μM. Molecular docking experiments were also performed to investigate the structure-activity relationship. Compounds 5 d and 7 b can be used as leads for further study and development of novel antitumor drugs.

Molecular docking and ADME evaluation of plant-based bioactive molecules targeting nonsense-mediated mRNA decay pathway factors to modulate tumorigenesis

Cancer is a global health challenge that requires continuous efforts to discover effective anticancer drugs. Phytochemicals are compounds found in plants that often have medicinal properties. They possess a wide range of bioactive properties, including anticancer activity. Their multiple mechanisms of action in different physiological processes in humans make them promising candidates in the anticancer therapeutics development. The presence of these compounds makes plants valuable resources for traditional medicine and modern pharmaceutical research as well. Natural products from plants and marine sources are being used to find new anticancer agents. In humans, different cellular pathways are involved in the tumorigenesis process. Many studies have shown the role of the nonsense-mediated mRNA decay (NMD) pathway in the process of tumorigenesis. This NMD pathway is controlled by multiple proteins. In this study, we conducted a molecular docking analysis of 50 phytochemicals against the human NMD factor up-frameshit2 (UPF2) protein. The results of the molecular docking experiment and ADME properties indicate that 4 of these molecules (Genistein, Trihydroxyflavone, Baicalein and Epigallocatechin) have the potential to modulate the NMD pathway. Furthermore, these molecules comply with Lipinski's rule of five. The effects of these 4 phytochemicals may be further evaluated using in vitro and in vivo methods for novel anticancer therapeutic development.

A spatial hierarchical network learning framework for drug repositioning allowing interpretation from macro to micro scale

Biomedical network learning offers fresh prospects for expediting drug repositioning. However, traditional network architectures struggle to quantify the relationship between micro-scale drug spatial structures and corresponding macro-scale biomedical networks, limiting their ability to capture key pharmacological properties and complex biomedical information crucial for drug screening and therapeutic discovery. Moreover, challenges such as difficulty in capturing long-range dependencies hinder current network-based approaches. To address these limitations, we introduce the Spatial Hierarchical Network, modeling molecular 3D structures and biological associations into a unified network. We propose an end-to-end framework, SpHN-VDA, integrating spatial hierarchical information through triple attention mechanisms to enhance machine understanding of molecular functionality and improve the accuracy of virus-drug association identification. SpHN-VDA outperforms leading models across three datasets, particularly excelling in out-of-distribution and cold-start scenarios. It also exhibits enhanced robustness against data perturbation, ranging from 20% to 40%. It accurately identifies critical motifs for binding sites, even without protein residue annotations. Leveraging reliability of SpHN-VDA, we have identified 25 potential candidate drugs through gene expression analysis and CMap. Molecular docking experiments with the SARS-CoV-2 spike protein further corroborate the predictions. This research highlights the broad potential of SpHN-VDA to enhance drug repositioning and identify effective treatments for various diseases.

Mechanistic exploration of bioactive constituents in Gnetum gnemon for GPCR-related cancer treatment through network pharmacology and molecular docking

G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that have gained considerable attention as drug targets, particularly in cancer treatment. In this study, we explored the capacity of bioactive compounds derived from Gnetum gnemon (GG) for the development of of pharmaceuticals targeting GPCRs within the context of cancer therapy. Integrated approach combined network pharmacology and molecular docking to identify and validate the underlying pharmacological mechanisms. We retrieved targets for GG-derived compounds and GPCRs-related cancer from databases. Subsequently, we established a protein-protein interaction (PPI) network by mapping the shared targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to predict the mechanism of action of these targets. Molecular docking was conducted to validate our findings. We identified a total of 265 targets associated with GG-derived bioactive compounds for the treatment of GPCRs-related cancer. Functional enrichment analysis revealed the promising therapeutic effects of these targets on GPCRs-related cancer pathways. The PPI network analysis identified hub targets, including MAPK3, SRC, EGFR, STAT3, ESR1, MTOR, CCND1, and PPARG, which demonstrate as treatment targets for GPCRs-related cancer using GG-derived compounds. Additionally, molecular docking experiments demonstrated the strong binding affinity of gnetin A, gnetin C, (-)-viniferin, and resveratrol dimer, thus inhibiting MAPK3, SRC, EGFR, and MTOR. Survival analysis established the clinical prognostic relevance of identified hub genes in cancer. This study presents a novel approach for comprehending the therapeutic mechanisms of GG-derived active compounds and thereby paving the way for their prospective clinical applications in the field of cancer treatment.

Evaluation of Selected Plant Phenolics via Beta-Secretase-1 Inhibition, Molecular Docking, and Gene Expression Related to Alzheimer’s Disease

Background: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against β-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as β-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC50 values 4.06 ± 0.68, 1.62 ± 0.12, 9.87 ± 1.01, and 3.16 ± 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors.

Troglitazone reduces intracellular Mycobacterium tuberculosis survival via macrophage autophagy through LKB1-AMPKα signaling.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined. Of these, only Troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the LKB1-AMPK signaling pathway. Molecular docking and co-immunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STRADA. Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid (INH)-resistant Mtb, and the combination of Trog and INH showed additive antibacterial effects against Mtb H37Rv. Taken together, anti-diabetic Trog may be repurposed as an HDT candidate and combined with first-line anti-TB drugs.

Design, synthesis, and biological investigations of new pyrazole derivatives as VEGFR2/CDK-2 inhibitors targeting liver cancer

New Series of N-Manniche bases 3,4 (a-c) and 5,6 (a-b) were synthesized through the reaction of benzaldehyde and amine with 3-methyl-4-(aryldiazenyl)-1H-pyrazol-5-ol derivatives 2(a-c), they were fully characterized by FT-IR, (1H, 13C) NMR data in addition to their mass spectra. The Structural Activity Relationship of the target compounds were examined for their cytotoxicity. Some newly synthesized compounds showed promising antiproliferation properties when tested against HepG2 cancer cells. Compounds 4a, 5a, and 6b showed potent cytotoxicity against HepG2 with IC50 values of 4.4, 3.46 and 2.52 µM compared to Sorafenib (IC50 = 2.051 µM) and Roscovitine (IC50 = 4.18 µM). Furthermore, they were safe against the THLE2 cells with higher IC50 values. Compound 6b exhibited promising dual VEGFR2/CDK-2 inhibition activities; it had an IC50 value of 0.2 μM with VEGFR2 inhibition of 93.2%, and it had an IC50 value of 0.458 μM with CDK-2 inhibition of 88.7%. In comparison to the untreated control group (0.95%), compounds 5a (38.32%) and 6b (42.9%) considerably increased the cell population in total apoptosis. In addition, compounds 5a and 6b arrested the cell population at G0-G1 and S phases, respectively. Molecular docking experiments confirmed the virtual binding mechanism of the most active drugs, which were found to have good binding affinities with both receptor active sites.

Synthesis, Biological activities, and Molecular docking Studies of 15-site Matrine Based Isatohydrazone Derivatives as Potential Anticancer Agents.

To further explore more active compounds, Matrine and Isatin derivatives have exhibited diverse biological activities. In this study, twenty-one 15-site matrine based isatohydrazone derivatives were designed, synthesized, and evaluated in their biological activities. In vitro, antiproliferative activity assays were carried out using the MTT assay against three human cell lines: human cervical cancer cells (HeLa), human colon cancer cells (HCT116), and non-small cell lung cancer cells (A549). Most of the target compounds displayed strong antiproliferative activities against the tested cells, surpassing matrine. Compound 5a exhibited the strongest antiproliferative activity, with IC50 values of 9.02±0.33 μM, 10.49±1.09 μM, and 15.23±0.12 μM against the respective cell lines. Experiments on cell cycle and apoptosis indicated that compound 5a induces cell cycle arrest in the G0/G1 phase and promotes cell apoptosis. Compound 5a also significantly inhibited cell colony formation and migration. Molecular docking experiments showed that compound 5a can form hydrogen bonds and hydrophobic interactions with the EGFR-related protein 7AEI.