Molecular Docking Research Articles

Investigating hub genes in the relationship between septic cardiomyopathy and cuproptosis and potential Chinese herbal drug candidates with bioinformatic tools.

The aim of this study was using bioinformatic tools to identify hub genes in the relationship between septic cardiomyopathy (SCM) and cuproptosis and predict potential Chinese herbal drug candidates. SCM datasets were downloaded from the gene expression omnibus. Cuproptosis related genes were collected from a research published on Science in March, 2022. The expression profiles of genes related to cuproptosis in SCM were extracted. Differentially expressed genes (DEGs) were analyzed using R package limma. A single-sample gene set enrichment analysis was conducted to measure the correlation between DEGs and immune cell infiltration. Hub genes were screened out by random forest model. Finally, HERB database and COREMINE database were used to predict Chinese herbal drugs for hub genes and carry out molecular docking. A total of 9 DEGs were identified. Cuproptosis differential genes PDHB, DLAT, DLD, FDX1, GCSH, LIAS were significantly correlated with one or more cells and their functions in immune infiltration. The random forest model screened pyruvate dehydrogenase E1 beta subunit (PDHB) as the hub gene. PDHB was negatively correlated with Plasmacytoid dendritic cell infiltration. Pyruvic acid, rhodioloside and adenosine were predicted with PDHB as the target, and all three components are able to bind to PDHB. Cuproptosis related gene PDHB is associated with the occurrence and immune infiltration of septic cardiomyopathy. Rhodioloside and other Chinese herbal drugs may play a role in the treatment of SCM by regulating the expression of PDHB.

Exploring the pathways of drug repurposing and Panax ginseng treatment mechanisms in chronic heart failure: a disease module analysis perspective.

Chronic Heart Failure (CHF) is a significant global public health issue, with high mortality and morbidity rates and associated costs. Disease modules, which are collections of disease-related genes, offer an effective approach to understanding diseases from a biological network perspective. We employed the multi-Steiner tree algorithm within the NeDRex platform to extract CHF disease modules, and subsequently utilized the Trustrank algorithm to rank potential drugs for repurposing. The constructed disease module was then used to investigate the mechanism by which Panax ginseng ameliorates CHF. The active constituents of Panax ginseng were identified through a comprehensive review of the TCMSP database and relevant literature. The Swiss target prediction database was utilized to determine the action targets of these components. These targets were then cross-referenced with the CHF disease module in the STRING database to establish protein-protein interaction (PPI) relationships. Potential action pathways were uncovered through Gene Ontology (GO) and KEGG pathway enrichment analyses on the DAVID platform. Molecular docking, the determination of the interaction of biological macromolecules with their ligands, and visualization were conducted using Autodock Vina, PLIP, and PyMOL, respectively. The findings suggest that drugs such as dasatinib and mitoxantrone, which have low docking scores with key disease proteins and are reported in the literature as effective against CHF, could be promising. Key components of Panax ginseng, including ginsenoside rh4 and ginsenoside rg5, may exert their effects by targeting key proteins such as AKT1, TNF, NFKB1, among others, thereby influencing the PI3K-Akt and calcium signaling pathways. In conclusion, drugs like dasatinib and midostaurin may be suitable for CHF treatment, and Panax ginseng could potentially mitigate the progression of CHF through a multi-component-multi-target-multi-pathway approach. Disease module analysis emerges as an effective strategy for exploring drug repurposing and the mechanisms of traditional Chinese medicine in disease treatment.

Effective delivery of miR-150-5p with nucleus pulposus cell-specific nanoparticles attenuates intervertebral disc degeneration.

The use of gene therapy to deliver microRNAs (miRNAs) has gradually translated to preclinical application for the treatment of intervertebral disc degeneration (IDD). However, the effects of miRNAs are hindered by the short half-life time and the poor cellular uptake, owing to the lack of efficient delivery systems. Here, we investigated nucleus pulposus cell (NPC) specific aptamer-decorated polymeric nanoparticles that can load miR-150-5p for IDD treatment. The role of miR-150-5p during disc development and degeneration was examined by miR-150-5p knockout (KO) mice. Histological analysis was undertaken in disc specimens. The functional mechanism of miR-150-5p in IDD development was investigated by qRT-PCR assay, Western blot, coimmunoprecipitation and immunofluorescence. NPC specific aptamer-decorated nanoparticles was designed, and its penetration, stability and safety were evaluated. IDD progression was assessed by radiological analysis including X-ray and MRI, after the annulus fibrosus needle puncture surgery with miR-150-5p manipulation by intradiscal injection of nanoparticles. The investigations into the interaction between aptamer and receptor were conducted using mass spectrometry, molecular docking and molecular dynamics simulations. We investigated NPC-specific aptamer-decorated polymeric nanoparticles that can bind to miR-150-5p for IDD treatment. Furthermore, we detected that nanoparticle-loaded miR-150-5p inhibitors alleviated NPC senescence in vitro, and the effects of the nanoparticles were sustained for more than 3months in vivo. The microenvironment of NPCs improves the endo/lysosomal escape of miRNAs, greatly inhibiting the secretion of senescence-associated factors and the subsequent degeneration of NPCs. Importantly, nanoparticles delivering miR-150-5p inhibitors attenuated needle puncture-induced IDD in mouse models by targeting FBXW11 and inhibiting TAK1 ubiquitination, resulting in the downregulation of NF-kB signaling pathway activity. NPC-targeting nanoparticles delivering miR-150-5p show favorable therapeutic efficacy and safety and may constitute a promising treatment for IDD.

Exploring the mechanism of cardiorenal protection with finerenone based on network pharmacology.

Large prospective trials have demonstrated that finerenone could reduce the risk of cardiovascular death and progression of renal failure among patients with chronic kidney disease (CKD) associated heart failure (HF) and/or type 2 diabetes mellitus (T2DM). The aim of this study was to explore the molecular mechanism of finerenone in the treatment of cardiorenal diseases through network pharmacology. The STITH, SwissTargetPrediction, PharmMapper, DrugBank and ChEMBL databases were used to screen the targets of finerenone. The diseases-related targets were retrieved from the DisGeNET, GeneCards, CTD, OMIM and MalaCards databases. The protein-protein interaction (PPI) network was conducted with STRING database and Cytoscape software. The clusterProfiler R package was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The interactions of key targets and finerenone were analyzed by molecular docking in Autodock software. Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. Histopathology of myocardial and renal tissues were observed by hematoxylin-eosin (HE) staining, and detection of protein expressions was conducted using western blotting. A total of 111 potential cardiorenal targets of finerenone were identified. The main mechanisms of action may be associated with lipid and atherosclerosis, fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications and diabetic cardiomyopathy. The hub targets demonstrated by the PPI network were CASP3, ALB, MMP9, EGFR, ANXA5, IGF1, SRC, TNFRSF1A, IL2 and PPARG, and the docking results suggested that finerenone could bind to these targets with high affinities. HE staining revealed the cardiorenal protection of finerenone on diabetic mice. In addition, the protein expressions of CASP3 and EGFR were increased while ALB was decreased in myocardial and renal tissues in diabetic mice compared with control mice, which were reversed by finerenone. This study suggested that finerenone exerts cardiorenal benefits through multiple targets and pathways.

Non-clinical investigations about cytotoxic and anti-platelet activities of gamma-terpinene.

Gamma-terpinene (γ-TPN) is a cyclohexane monoterpene isolated from plant essential oils, such as tea tree (Melaleuca alternifolia), oregano (Origanum vulgare), rosemary (Rosmarinus officinalis L.), thyme (Thymus vulgaris Marchand), and eucalyptus (Eucalyptus sp.). Terpenes are widely studied molecules pharmacologically active on the cardiovascular system, hemostasis, and antioxidant actions. Herein, it was investigated the cytotoxic and antiplatelet activity of γ-TPN using different non-clinical laboratory models. For in silico evaluation, the PreADMET, SwissADME, and SwissTargetPrediction softwares were used. Molecular docking was performed using the AutoDockVina and BIOVIA Discovery Studio databases. The cytotoxicity of γ-TPN was analyzed by the MTT assay upon normal murine endothelial SVEC4-10 and fibroblast L-929 cells. Platelet aggregation was evaluated with platelet-rich (PRP) and platelet-poor (PPP) plasma from spontaneously hypertensive rats (SHR), in addition to SVEC4-10 cells pre-incubated with γ-TPN (50, 100, and 200 µM) for 24 h. SHR animals were pre-treated by gavage with γ-TPN for 7 days and divided into four groups (negative control, 25, 50, and 100 mg/kg). Blood samples were collected to measure nitrite using the Griess reagent. Gamma-TPN proved to be quite lipid-soluble (Log P = +4.50), with a qualified profile of similarity to the drug, good bioavailability, and adequate pharmacokinetics. It exhibited affinity mainly for the P2Y12 receptor (6.450 ± 0.232 Kcal/mol), moderate cytotoxicity for L-929 (CC50 = 333.3 µM) and SVEC 4-10 (CC50 = 366.7 µM)cells. The presence of γ-TPN in SVEC 4-10 cells was also able to reduce platelet aggregation by 51.57 and 44.20% at lower concentrations (50 and 100 µM, respectively). Then, γ-TPN has good affinity with purinergic receptors and an effect on the reversal of platelet aggregation and oxidative stress, being promising and safe for therapeutic targets and subsequent studies on the control of thromboembolic diseases.

Identification of DPP-IV inhibitory peptides derived from buffalo colostrum: Mining through bioinformatics, in silico and in vitro approaches.

Bioactive peptides derived from foods provide physiological health benefits beyond nutrition. This study focused on profiling small peptide inhibitors against two key serine proteases, dipeptidyl peptidase-IV (DPP-IV) and prolyl oligopeptidase (POP). DPP-IV is a well-known protein involved in diverse pathways regulating inflammation, renal, cardiovascular physiology, and glucose homeostasis. POP is yet another key target protein for neurodegenerative disorders. The study evaluated peptide libraries of buffalo colostrum whey and fat globule membrane proteins derived from pepsin and pepsin-pancreatin digestion through in silico web tools and structure-based analysis by molecular docking and binding free-energy estimation, followed by in vitro assay for DPP-IV inhibition for the lead peptides. The bioinformatic study indicated 49 peptides presented motifs with DPP-IV inhibition while 5 peptides with sequences for POP inhibition. In the molecular docking interactions study, 22 peptides interacted with active site residues of DPP-IV and 3 peptides with that of POP. The synthesized peptides, SFVSEVPEL and LTFQHNF inhibited DPP-IV in vitro with an IC50 of 193.5 μM and 1.782 mM, respectively. The study revealed the key residues for inhibition of DPP-IV and POP thus affirming the DPP-IV inhibitory potential of milk-derived peptides.

Theoretical Investigation and Design of Bioactive Quinoline Derivatives as Inhibitors of DNA Gyrase of Salmonella typhi

The ever-increasing rate of resistance to existing antibiotics by Salmonella typhi has made the search for novel drug candidates a necessity. In this study, Molecular docking technique was used to screen 18 bioactive quinoline derivatives against DNA gyrase of Salmonella typhi using PyRx graphical user interface of AutoDock Vina software. Ligand with the best binding affinity against the target macromolecule was used as prototype to design novel analogues with enhanced potencies. With the aid of Swiss ADME online server and Osiris DataWarrior v5.5.0 programme, the absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles of the ligands were evaluated and their electronic properties were computed using density functional theory (DFT) method of Spartan 14.0 software. Ligand 3 (L3) with the best binding affinity (TG) value of −10.5 kcal/mol was chosen as a prototype to design La and Lb with TG value of −10.7 kcal/mol and −10.8 kcal/mol; binding constant (ka) of 7.04 × 107 and 8.35 × 107 ; and dissociation constant (kd) of 1.42 x 10−8 and 1.2 × 10−8, respectively. When compared with ciprofloxacin (TG = −7.7 kcal/mol), the ligands could be more potent. Likewise, the ligands were found to possess excellent oral bioavailability and pharmacokinetic profiles. Furthermore, DFT calculations on La and Lb revealed that they possess highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap of 3.46 eV and 3.45 eV; and global electrophilicity index of 3.83 eV and 3.96 eV, respectively. The designed ligands tend to be consistent with all the validation protocols deployed in this study and as such could be recommended as novel drug candidates for treatment of Salmonella typhi induced salmonellosis.

Analysis of the anti-PCV2 mechanism of Lactobacillus acidophilus based on non-target metabolomics and high-throughput molecular docking

Analysis of the anti-PCV2 mechanism of Lactobacillus acidophilus based on non-target metabolomics and high-throughput molecular docking

Drug–target interaction prediction based on improved heterogeneous graph representation learning and feature projection classification

Drug–target interaction (DTI) identification is a complex process that is time-consuming, costly and frequently inefficient, with a low success rate, especially with wet-experimental methods. The prediction of DTI by calculational methods is an effective way to solve this problem. However, most existing methods regard drug–target pairs with unknown interaction relationship as negative samples, that the false negative samples will affect the AUC and AUPR evaluation, leading to performance misjudgment. Therefore, in this paper, a new DTI prediction method, DTI-HAN, is proposed to overcome the shortcoming and further improve the predictive performance. In the drug and target feature representation learning stage, this method constructs a drug–target heterogeneous network based on similarity and interaction relationship, and establishes meta-path, node-level and semantic-level bi-attention mechanism. To avoid introducing false negative examples, an improved loss function based only on known edges is proposed. In the DTI prediction stage, feature projection and fuzzy theory are introduced, and membership distribution function is estimated only depended on positive samples. Compared with the DTI prediction methods, DTI-GAT, DTI-GCN and DTI-GraphSAGE, as well as BLM, DTHybrid, SCMLKNN and FPSC-DTI, the experimental results on Enzyme, GPCR, Ion Channel and Nuclear Receptor 4 datasets showed that the DTI-HAN method can greatly improve the AUC and AUPR values on at least 3 datasets to each method. Furthermore, the novel top 100-pair of DTIs prediction were verified by KEGG, DrugBank, ChEMBL and SuperTarget databases, and obtained 21, 48, 61 and 28 validation records, respectively. The top-5 remaining unverified DTIs were performed molecular docking with AutoDock Vina, and the results showed that these drugs and targets have good binding properties. The code and data are available at https://github.com/Yu123456/DTI-HAN.

Ilicicolin C suppresses the progression of prostate cancer by inhibiting PI3K/AKT/mTOR pathway.

Aberrant activation of the PI3K/AKT pathway is a driving factor in the development of prostate cancer. Therefore, inhibiting the function of the PI3K/AKT signaling pathway is a strategy for the treatment of prostate cancer. Ilicicolin C is an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501. Which has anti-inflammatory activity, but its activity against prostate cancer has not yet been elucidated. MTT assay, plate clone-formation assay, flow cytometry and real-time cell analysis technology were used to detect the effects of ilicicolin C on cell viability, proliferation, apoptosis and migration of prostate cancer cells. Molecular docking software and surface plasmon resonance technology were used to analyze the interaction between ilicicolin C and PI3K/AKT proteins. Western blot assay was performed to examine the changes in protein expression. Finally, QikProp software was used to simulate the process of ilicicolin C in vivo, and a zebrafish xenograft model was used to further verify the anti-prostate cancer activity of ilicicolin C in vivo. Ilicicolin C showed cytotoxic effects on prostate cancer cells, with the most significant effect on PC-3 cells. Ilicicolin C inhibited proliferation and migration of PC-3 cells. It could also block the cell cycle and induce apoptosis in PC-3 cells. In addition, ilicicolin C could bind to PI3K/AKT proteins. Furthermore, ilicicolin C inhibited the expression of PI3K, AKT and mTOR proteins and could also regulate the expression of downstream proteins in the PI3K/AKT/mTOR signaling pathway. Moreover, the calculations speculated that ilicicolin C was well absorbed orally, and the zebrafish xenograft model confirmed the in vivo anti-prostate cancer effect of ilicicolin C. Ilicicolin C emerges as a promising marine compound capable of inducing apoptosis of prostate cancer cells by counteracting the aberrant activation of PI3K/AKT/mTOR, suggesting that ilicicolin C may be a viable candidate for anti-prostate cancer drug development. These findings highlight the potential of ilicicolin C against prostate cancer and shed light on its mechanism of action.

An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs.

Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R2 and Q2 values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1-D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein-ligand complex.

A joint experimental and theoretical investigation of the binding mechanism between zein and folic acid in an ethanol–water solution

ABSTRACT The aim of the present study was to determine the binding mechanisms between zein and folic acid in an ethanol – water solution. Fluorescence spectroscopy demonstrated that folic acid quenched the fluorescence intensity of zein by both dynamic and static fluorescence quenching mechanisms, with static quenching playing a prominent role. The binding constants (Ka) of the zein-folic acid complex at 292, 302, and 312 K were evaluated to be 5.97 × 105, 3.00 × 105 and 1.54 × 105 L/mol, respectively. The process of folic acid binding zein was driven by ∆H0 = –51.24 kJ/mol, ∆S0 = –64.90 J/mol•K. Van der Waals forces and hydrogen bonding primarily governed the formation of the zein-folic acid complex. Confirmation of the complex formation was obtained via UV-visible absorption spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism spectroscopy, which also revealed alterations in the secondary structure of zein upon binding to folic acid. Measurements of particle size and zeta potential demonstrated an enhancement in the stability of the complex system. Scanning electron microscopy and transmission electron microscopy showed the complex to possess a spherical morphology, with significant changes in the zein’s morphology following its binding to folic acid. Additionally, zein increased the photostability of folic acid against UV light radiation. Molecular docking and molecular dynamics simulations were used to investigate the binding mechanisms involved further, and the results effectively elucidated the observed experimental phenomena. This research establishes a significant theoretical foundation for the utilization of zein as a system for delivering and safeguarding folic acid.

Inhibition of NF-kB and COX-2 by andrographolide regulates the progression of cervical cancer by promoting PTEN expression and suppressing PI3K/AKT signalling pathway

In the face of recent advances in Cervical cancer (CC) treatment, therapeutic and surgical procedures for CC management are still inadequate. In the current study for the first time Andrographolide (Andro) has been explored for its multitarget therapeutic efficacy on NF-kB, COX-2, and PI3K/AKT expressions together in CC. The expression levels of NF-kB, COX-2, PI3K and PTEN in the CC patient samples, both at mRNA and protein levels have shown significant association with poor survival and increased tumor aggressiveness. The binding efficacy of Andro was investigated using molecular docking and molecular dynamic simulations, and the protein and ligand complex for NF-kB and COX-2 has shown high binding energy. Andro displayed cytotoxicity by impeding the in-vitro proliferation of CC cells. Andro significantly supressed the NF-kB, COX-2, and PI3K expression and enhanced the expression levels of PTEN at protein levels in-vitro. Andro induced apoptosis in a dose dependent manner and significantly inhibited the migration and invasion of CC cells. Andro exhibited similar activity in-vivo and suppressed the CC tumor growth in xenograft C57BL/6 mice model. The anti-tumor activity of Andro, both in-vitro and in-vivo has shown considerable downregulation of NF-kB and COX-2 and induced apoptosis through impeding the PI3K/AKT signalling pathway. These findings from the above study projects, administration of Andro as an effective alternate safe compound to curtail and impede cervical cancer progression.

Potent inhibition of human and rat 17β-hydroxysteroid dehydrogenase 1 by curcuminoids and the metabolites: 3D QSAR and in silico docking analysis

ABSTRACT Curcumin, an extensively utilized natural pigment in the food industry, has attracted considerable attention due to its potential therapeutic effects, such as anti-tumorigenic and anti-inflammatory activities. The enzyme 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) holds a crucial position in oestradiol production and exhibits significant involvement in oestrogen-responsive breast cancers and endometriosis. This study investigated the inhibitory effects of curcuminoids, metabolites, and analogues on 17β-HSD1, a key enzyme in oestradiol synthesis. Screening 10 compounds, including demethoxycurcumin (IC50, 3.97 μM) and dihydrocurcumin (IC50, 5.84 μM), against human and rat 17β-HSD1 revealed varying inhibitory potencies. These compounds suppressed oestradiol secretion in human BeWo cells at ≥ 5–10 μM. 3D-Quantitative structure-activity relationship (3D-QSAR) and molecular docking analyses elucidated the interaction mechanisms. Docking studies and Gromacs simulations suggested competitive or mixed binding to the steroid or NADPH/steroid binding sites of 17β-HSD1. Predictive 3D-QSAR models highlighted the importance of hydrophobic regions and hydrogen bonding in inhibiting 17β-HSD1 activity. In conclusion, this study provides valuable insights into the inhibitory effects and mode of action of curcuminoids, metabolites, and analogues on 17β-HSD1, which may have implications in the field of hormone-related disorders.

DFT Analyses of arsylsemicarbazone group as functional compound for application as excellent fluorescent probes and medicament: study on virtual screening through molecular docking

DFT Analyses of arsylsemicarbazone group as functional compound for application as excellent fluorescent probes and medicament: study on virtual screening through molecular docking

Integration of bioinformatics analysis, molecular docking and animal experiments to study the therapeutic mechanisms of berberine against allergic rhinitis

Allergic rhinitis is a prevalent inflammatory condition that impacts individuals of all age groups. Despite reports indicating the potential of berberine in alleviating allergic rhinitis symptoms, the specific molecular mechanisms and therapeutic targets of berberine remain unclear. This research aims to explore the pharmacological mechanism of berberine in the treatment of allergic rhinitis through bioinformatic analyses and experimental validation. The research utilized public databases to identify potential targets of berberine. Furthermore, differentially expressed genes (DEGs) related to allergic rhinitis were pinpointed from the GSE52804 dataset. Through bioinformatics techniques, the primary targets were discovered and key KEGG and GO-BP pathways were established. To confirm the therapeutic mechanisms of berberine on allergic rhinitis, an OVA-induced allergic rhinitis model was developed using guinea pigs. We identified 32 key genes responsible for the effectiveness of berberine in treating allergic rhinitis. In addition, five central genes (Alb, Il6, Tlr4, Ptas2, and Il1b) were pinpointed. Further examination using KEGG and GO-BP pathways revealed that the main targets were primarily involved in pathways such as NF-kappa B, IL-17, TNF, and inflammatory response. Molecular docking analysis demonstrated that berberine exhibited strong affinity towards these five key targets. Furthermore, the expression levels of IL-6, TLR4, PTGS2, and IL-1β were significantly upregulated in the model group but downregulated following berberine treatment. This research has revealed the mechanism through which berberine combats allergic rhinitis and has identified its potential to regulate pathways linked to inflammation. These discoveries provide valuable insights for the development of novel medications for the treatment of allergic rhinitis.

Establishment of an at-line nanofractionation-based screening platform by coupling HPLC-MS/MS with high-throughput fluorescence polarization bioassay for natural SARS-CoV-2 fusion inhibitors

In this study, a novel at-line nanofractionation platform was established for screening SARS-CoV-2 fusion inhibitors from natural products for the first time by combining HPLC-MS/MS with high-throughput fluorescence polarization (FP) bioassay. A time-course FP bioassay in 384 well-plates was conducted in parallel with MS/MS to simultaneously obtain chemical and biological information of potential fusion inhibitors in Lonicerae Japonicae Flos (LJF) and Lianhua Qingwen capsules (LHQW). Semi-preparative liquid chromatography and orthogonal HPLC separation were employed to enrich and better identify the co-eluted components. After comprehensive evaluation and validation, 28 potential SARS-CoV-2 fusion inhibitors were screened out and identified. Several compounds at low micromolar activity were validated by in vitro inhibitory assay, molecular docking, cytotoxicity test, and pseudovirus assay. Moreover, four potential dual-target inhibitors against influenza and COVID-19 were discovered from LJF using this method, offering novel insights for the development of future pharmaceuticals targeting epidemic respiratory diseases.

Unravelling the molecular mechanistic pathway underlying the anticancer effects of kaempferol in colorectal cancer: a reverse pharmacology network approach.

Colorectal cancer (CRC) is the third most diagnosed and highly fatal malignancy, presenting serious health concerns worldwide. The search for an effective cure for CRC is challenging and poses a serious concern. Kaempferol is a potent anti-cancerous bioactive compound often suggested for treating various cancers, including CRC. However, its underlying molecular mechanism against CRC remains unclear. The present study delves into kaempferol's molecular pathways and underlying molecular mechanisms against CRC targets. The target protein-coding genes for kaempferol were retrieved, and the CRC-associated genes were curated. Twelve common targets with a disease specificity index of > 0.6 were validated for their protein expression at different stages of CRC. Over-expressed USP1, SETD7, POLH, TDP1 and RACGAP1 were selected for further studies. The binding affinities of kaempferol to the corresponding proteins were evaluated using molecular docking and Molecular Dynamics (MD) simulations. SETD7 exhibited the highest binding affinity with the lowest binding energy (-8.06kcal/mol). Additionally, the MD simulation, and MM-PBSA conferred SETD7-kaempferol complex had the least root-mean-square deviation with lower interaction energy and higher conformational stability. The protein-protein interaction of SETD7 constructed revealed direct interactors, namely, DNMT1, FOXO1, FOXO3, FOXO4, H3-3B, H3-4, H3C12, H3C13, SETD7, SIRT1 and TP53, have a potential role in cancer progression through FOXO signalling. In summary, our study revealed kaempferol's multi-target and synergistic effect on multiple CRC targets and its underlying mechanisms. Finally, the study recommends in-vitro and in-vivo trials for validation of anti-cancerous drugs for CRC.

Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is a malignant tumor of the urinary system. To explore the potential mechanisms of DHODH in ccRCC, we analyzed its molecular characteristics using public databases. TCGA pan-cancer dataset was used to analyze DHODH expression in different cancer types and TCGA ccRCC dataset was used to assess differential expression, prognosis correlation, immune infiltration, single-gene, and functional enrichment due to DHODH. The GSCALite and CellMiner databases were employed to explore drugs and perform molecular docking analysis with DHODH. Protein–protein interaction networks and ceRNA regulatory networks of DHODH were constructed using multiple databases. The effect of DHODH on ccRCC was confirmed in vitro. DHODH was highly expressed in ccRCC. Immune infiltration analysis revealed that DHODH may be involved in regulating the infiltration of immunosuppressive cells such as Tregs. Notably, DHODH influenced ccRCC progression by forming regulatory networks with molecules, such as hsa-miR-26b-5p and UMPS and significantly enhanced the malignant characteristics of ccRCC cells. Several drugs, such as lapatinib, silmitasertib, itraconazole, and dasatinib, were sensitive to DHODH expression and exhibited strong molecular binding with it. Thus, DHODH may promote ccRCC progression and is a candidate effective therapeutic target for ccRCC.

TEMPLATE-ENGINEERED TRIVALENT IRON AND CHROMIUM CONTAINING MACROCYCLIC COMPLEXES: CHARACTERIZATION AND IN VITRO STUDIES

A novel series of tetraaza macrocyclic complexes of biological importance was synthesized by “in situ” template reaction between triethylenetetramine and dibenzoylmethane in the presence of trivalent Fe and Cr metal salts in 1:1:1 molar ratio. These complexes are represented by molecular formula [M(C[Formula: see text]H[Formula: see text]N[Formula: see text]X]X2; [Formula: see text](III) and Cr(III); [Formula: see text], NO[Formula: see text], −OAc; C[Formula: see text]H[Formula: see text]N[Formula: see text] ligand. The reported complexes were characterized by using various physicochemical and spectroscopic techniques including elemental analyses, molar conductance, thermo-gravimetric analysis, FTIR, UV–Visible and mass spectral studies. The results obtained from analytical techniques and spectroscopic techniques together suggested the complexes have a square pyramidal geometry. Various computational studies were performed including molecular docking and modeling. Further, macrocyclic complexes were also screened for their “in vitro” antimicrobial activity against selected bacterial and fungal strains. The antioxidant activity of these complexes was also evaluated. Some of the complexes were found to possess remarkable antimicrobial activity and antioxidant activity. However, complex [Fe(C[Formula: see text]H[Formula: see text]N[Formula: see text](NO[Formula: see text]](NO[Formula: see text] was found to be most potent against selected bacterial and fungal strains. On the other hand, complex [Cr(C[Formula: see text]H[Formula: see text]N[Formula: see text](NO[Formula: see text]](NO[Formula: see text] was found to show best antioxidant activity with lowest value of IC[Formula: see text].