Target Proteins Research Articles

Graph-DTI: A New Model for Drug-target Interaction Prediction Based on Heterogenous Network Graph Embedding.

In this study, we aimed to develop a new end-to-end learning model called Graph-Drug-Target Interaction (DTI), which integrates various types of information in the heterogeneous network data, and to explore automatic learning of the topology-maintaining representations of drugs and targets, thereby effectively contributing to the prediction of DTI. Precise predictions of DTI can guide drug discovery and development. Most machine learning algorithms integrate multiple data sources and combine them with common embedding methods. However, the relationship between the drugs and target proteins is not well reported. Although some existing studies have used heterogeneous network graphs for DTI prediction, there are many limitations in the neighborhood information between the nodes in the heterogeneous network graphs. We studied the drug-drug interaction (DDI) and DTI from DrugBank Version 3.0, protein-protein interaction (PPI) from the human protein reference database Release 9, drug structure similarity from Morgan fingerprints of radius 2 and calculated by RDKit, and protein sequence similarity from Smith-Waterman score. Our study consists of three major components. First, various drugs and target proteins were integrated, and a heterogeneous network was established based on a series of data sets. Second, the graph neural networks-inspired graph auto-encoding method was used to extract high-order structural information from the heterogeneous networks, thereby revealing the description of nodes (drugs and proteins) and their topological neighbors. Finally, potential DTI prediction was made, and the obtained samples were sent to the classifier for secondary classification. The performance of Graph-DTI and all baseline methods was evaluated using the sums of the area under the precision-recall curve (AUPR) and the area under the receiver operating characteristic curve (AUC). The results indicated that Graph-DTI outperformed the baseline methods in both performance results. Compared with other baseline DTI prediction methods, the results showed that Graph-DTI had better prediction performance. Additionally, in this study, we effectively classified drugs corresponding to different targets and vice versa. The above findings showed that Graph-DTI provided a powerful tool for drug research, development, and repositioning. Graph- DTI can serve as a drug development and repositioning tool more effectively than previous studies that did not use heterogeneous network graph embedding.

Palladium catalysed cross coupling reactions on 2,3-isoxazol-17α-ethynyltestosterone, their anti-cancer activity, molecular docking studies and ADMET analysis

In the current study, the Sonogashira coupling reaction of danazol with aryl halides was carried out, yielding new aryl substituted danazol derivatives. The synthetic compounds were examined for anti-cancer potential on the HeLa human cervical cancer cell line, and they showed promising cytotoxic action. Synthesized compounds 2, 4 and 5 inhibited the growth of HeLa cervical cancer cells, potentially making them effective anti-cancer drugs in the future. Furthermore, molecular docking studies were performed to evaluate the inhibitory impact of danazol derivatives on the Human Papillomavirus (HPV) target protein (1F9F). The docking results showed a significant inhibitory action against the cervical cancer protein (1F9F). The binding energy (ΔG) values of 1, 2, 3, 4 and 5 against the protein 1F9F were −8.01, −8.70, −9.43, −9.58 and −9.75 kcal/mol, indicating a high affinity of the synthesized compounds to bind with the HPV target proteins compared to their parent compound danazol (1). ADMET analyses of all derivatives have also been carried out

Interplay of CDKs and Cyclins with glycolytic regulatory enzymes PFK and PK.

In plants, as in all eukaryotes, the cell cycle is regulated by the heterodimer formed by cyclins (Cycs) and cyclin-dependent kinases (CDKs), that phosphorylate serine/threonine residues in target proteins. The extensive involvement of these heterodimers in nuclear cell cycle-related processes has been demonstrated. However, recent findings have linked Cyc-CDK complexes to the regulation of cytosolic processes, including various metabolic pathways, suggesting close coordination between the cell cycle and catabolic/anabolic processes to maintain cellular energy homeostasis.This study extends the analysis of Cyc-CDK complex regulation in maize to two key regulators of glycolysis: phosphofructose kinase (PFK) and pyruvate kinase (PK). Both are cytosolic enzymes, highly regulated positively and negatively by different metabolites, showing a similar activation pattern in their homotetrameric form and low activity when as dimers/monomers. Each enzyme exhibits two putative minimal phosphorylation motives for Cyc-CDKs, conserved in some plant species and in four (PFK) and three (PK) isoforms in maize. This work demonstrates that both enzymes are active with fluctuating levels of activity along maize germination; also, that they associate with different maize Cycs and CDKs as demonstrated by pull-down assays, as well as their in vitro phosphorylation by recombinant CycD;2-CDKA or CycD2;2-CDKB complexes. Additionally, the inhibition of PFK and PK activity following phosphorylation by active Cycs-CDKB complexes obtained by immunoprecipitation from imbibed embryonic axis protein extracts suggests a narrow and negative regulation of glycolysis as the cell cycle progresses. A decreased carbon flow through this pathway is proposed to divert carbon from sugars towards the oxidative pentose phosphate pathway, thereby promoting de novo nucleic acid synthesis precursors to stimulate cell cycle progression.

Licochalcone A loaded multifunctional chitosan hyaluronic acid hydrogel with antibacterial and inflammatory regulating effects to promote wound healing

The wound healing process is characterized by persistent infection and long-term inflammation. The licochalcone A (LicA) has the potential for skin wound healing and needs a good drug-loading platform to apply its antibacterial and anti-inflammatory effects. In this study, the LicA@chitosan (CS) -hyaluronic acid (HA) hydrogel with antibacterial and anti-inflammatory was developed for wound healing in mice. The SEM displayed that the hydrogel had an obvious porous structure and was very suitable to be used as a delivery carrier for LicA. The FTIR results suggested that the LicA can be effectively loaded in the CS-HA hydrogel. Variable strain scanning, frequency scanning and temperature scanning indicated that the LicA@CS-HA hydrogel can maintain the gel state. The LicA@CS-HA hydrogel had good biological safety, can inhibit the activity of Escherichia coli and Staphylococcus aureus, and can release LicA stably. The LicA@CS-HA hydrogel also has good adhesion and hemostatic properties. Finally, the LicA@CS-HA hydrogel significantly accelerated wound healing in mice skin injury model, and reduced inflammation and orderly collagen deposition were observed by HE and Masson staining. The immunohistochemistry indicated that the LicA@CS-HA hydrogel induced the positive expression of CD31, VEGF, and HIF-1α promoted neovascularization. The LicA@CS-HA hydrogel also down-regulated the expression of M1 macrophage markers CD86, IL-6, and TNF-α, and increased the expression of M2 macrophage markers CD206, IL-4, and IL-10 proteins. The molecular docking demonstrated that the target proteins had better binding activity to LicA. Collectively, the LicA@CS-HA hydrogel has broad application prospects in promoting wound healing.

Theoretical study based on molecular docking to investigate the potential interaction of known antiviral food components with SARS-CoV-2 proteins

Many food components have antiviral activity, but in most cases, studies in the literature do not report detailed investigations of molecular mechanisms. We performed a comprehensive molecular docking study to investigate the potential interaction of several food molecules, selected for their known antiviral activity, with twelve SARS-CoV-2 target proteins (NSP3, NSP5, NSP7, NSP8, NSP9, NSP10, NSP12, NSP15, NSP16, ORF7A, protein N, and Spike protein). The results suggest that some molecules, particularly β-carotene, all-trans-retinoic acid (ATRA), epigallocatechin 3-gallate and kaempferol, can interact with SARS-CoV-2 protein targets. The study opens new insights into the molecular mechanisms underlying the antiviral properties of food components.

Small molecule inhibitors of IL-1R1/IL-1β interaction identified via transfer machine learning QSAR modelling

The human interleukin-1 receptor I (IL-1R1) is a cytokine receptor recognized by interleukin 1β (IL-1β), among other cytokines. Over activation of IL-1R1 has been implicated in various inflammatory conditions. This research aims to identify small-molecule inhibitors targeting the hIL1R1/IL1β interaction, employing a multi-task transfer learning approach for quantitative structure-activity relationship (QSAR) modelling. A comprehensive bioactivity dataset from functionally related proteins was utilised to build a robust ensemble machine learning model for predicting IC50 values against the target protein. Despite the availability of antibody-based therapies, the absence of orally available small-molecule inhibitors necessitates their development. By combining model predictions with docking and simulation approaches, the interleukin-1 receptor inhibitor (IRI-1) emerged as a lead compound. It potently inhibited human IL1-R1 with micromolar activity in THP-1 and Saos-2 cells and demonstrated good biocompatibility. Western blot analysis revealed that IRI-1 inhibits IL-1β-mediated phosphorylation of IL1-R1, JNK, IRAK-4, and ERK in THP-1 cells. Furthermore, molecular dynamics simulations confirmed the structural stability of the protein-ligand complexes. This study highlights the effectiveness of multi-task transfer learning approaches for building robust QSAR models against novel proteins or those with limited bioactivity data, such as hIL-1β/IL-1R1 protein.

Molecular Modelling of Resveratrol Derivatives with SIRT1 for the Stimulation of Deacetylase Activity.

Resveratrol is a polyphenol that is found in plants and has been proposed to have a potential therapeutic effect through the activation of SIRT1, which is a crucial member of the mammalian NAD+ -dependent deacetylases. However, how its activity is enhanced toward specific substrates by resveratrol derivatives has not been studied. This study aimed to evaluate the types of interaction of resveratrol and its derivatives with SIRT1 as the target protein, as well as to find out the best ligand with the strangest interaction with SIRT1. In this study, we employed the extensive molecular docking analysis using AutoDock Vina to comparatively evaluate the interactions of resveratrol derivatives (22 molecules from the ZINC database) as ligands with SIRT1 (PDB ID: 5BTR) as a receptor. The ChemDraw and Chem3D tools were used to prepare 3D structures of all ligands and energetically minimize them by the MM2 force field. The molecular docking and visualizations showed that conformational change in resveratrol derivatives significantly influenced the parameter for docking results. Several types of interactions, including conventional hydrogen bonds, carbon-hydrogen bonds, Pi-donor hydrogen bonds, and Pi-Alkyl, were found via docking analysis of resveratrol derivatives and SIRT1 receptors. The possible activation effect of resveratrol 4'-(6-galloylglucoside) with ZINC ID: ZINC230079516 with higher binding energy score (-46.8608 kJ/mol) to the catalytic domain (CD) of SIRT1 was achieved at the maximum value for SIRT1, as compared to resveratrol and its other derivatives. Finally, resveratrol 4'-(6-galloylglucoside), as a derivative for resveratrol, has stably interacted with the CD of SIRT1 and might be a potential effective activator for SIRT1.

Caseinolytic protease P (ClpP) is a c-di-GMP effector protein modulating motility, biofilm and virulence in Stenotrophomonas maltophilia

Cyclic di-GMP (c-di-GMP) is a crucial secondary messenger in bacterial cells, profoundly impacting various physiological and biochemical processes. Numerous studies showed that c-di-GMP regulates specific bacterial pathways by interacting with related effectors, and modulating their functions at the transcriptional or post-transcriptional levels. How c-di-GMP regulates bacterial global metabolism remains to be explored. In this study, we employed c-di-GMP pull-down assays in Stenotrophomonas maltophilia. We identified one target protein as caseinolytic protease P (ClpP), a highly conserved protease in both eukaryotic and prokaryotic cells, playing an essential role in global cellular metabolism regulation. We examined the binding site of c-di-GMP with ClpP and demonstrated that c-di-GMP enhances the peptidase activity of ClpP. Furthermore, ClpP is shown to play a vital regulatory role in bacterial motility and can activate bacterial motility in the presence of high c-di-GMP level. This research demonstrates that c-di-GMP mediates global regulation at the metabolic level via protein homeostasis. Additionally, it offers critical insights into the functional role of ClpP, which may inform the development of novel antimicrobial strategies.

N6-methyladenosine (m6A)-circHECA from secondary hair follicle of cashmere goats: identification, regulatory network and expression regulated potentially by methylation of its host gene promoter.

The objective of this study was to identify the N6-methyladenosine (m6A)- circHECA molecule in secondary hair follicles (SHFs) of cashmere goats, and generate its potential regulatory network, as well as explore the potential relationship between transcriptional pattern of m6A-circHECA and promoter methylation of its host gene (HECA). The validation of circHECA m6A sites was performed using methylation immunoprecipitation (Me-RIP) along with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) technique. The nucleus and cytoplasm localizations of m6AcircHECA were performed using SHF stem cells of cashmere goats with RT-qPCR analysis. Based on in-silico analysis, the regulatory networks of m6A-circHECA were generated with related signal pathway enrichment. The methylation level of promoter region of m6A-circHECA host gene (HECA) was assessed by the bisulfite sequencing PCR (BSPPCR) technique. The m6A-circHECA was confirmed to contain four m6A modification sites including m6A-213, m6A-297, m6A-780, and m6A-927, and it was detected mainly in cytoplasm of the SHF stem cells of cashmere goats. The integrated regulatory network analysis showed directly or indirectly complex regulatory relationships between m6A-circHECA of cashmere goats and its potential target molecules: miRNAs, mRNAs, and proteins. The regulatory network and pathway enrichment indicated that m6A-circHECA might play multiple roles in the SHF physiology process of cashmere goats through directly or indirectly interacting or regulating its potential target molecules. A higher methylation level of promoter region of HECA gene in SHFs of cashmere goats might cause the lower expression of m6A-circHECA. The m6A-circHECA might play multiple roles in SHF physiology process of cashmere goats through miRNA mediated pathways along with directly or indirectly interaction with its target proteins. The promoter methylation of m6A-circHECA host gene (HECA) most likely was implicated in its expression inhibition in SHFs of cashmere goats.

Insight into the molecular mechanism of anti-breast cancer therapeutic potential of substituted salicylidene-based compounds using cell-based assays and molecular docking studies.

Targeting oxidative stress and inflammatory signaling pathways is an effective cancer prevention and therapy approach. The mechanism of action of synthesized salicylidene-based compounds was investigated in regulating key molecular targets of breast cancer development. Compounds (1), (4), (5), and (7) were found to be more cytotoxic to MCF-7 and 4T1 cells compared to non-cancerous Chang liver cells, while these compounds were cytotoxic to MDA-MB-231 cells, but with poor selectivity. The colony formation assay indicated that bioactive compounds induced significant damage to breast cancer cells, as observed by a reduction in the number of colonies compared to control cells. By inducing a concentration and time-dependent increase of luminescence and fluorescence of phosphatidylserine, and activating the expression of caspases-3, -7, -8, -9 in breast cancer cells, (1) and (7) have shown to induce caspase-dependent apoptosis. The downregulation of NF-kB-p65 and an upregulation of TP53 expression after exposure to bioactive compounds, demonstrated the suppression of two key targets of breast cancer development. Molecular docking studies revealed that selected protein targets strongly interact with bioactive compounds, and the estimated inhibition constants (Ki) of JAK2, STAT3, COX-2, HPV31 E6, EGFR1, TP53, and PARP1 were significantly decreased compared to acetylsalicylic acid. This could be a clear indication that these protein targets are implicated with antiproliferative efficacy, thereby warranting the potential of (1) and (7) to be used as anti-breast cancer drug candidates.

The inhibition of rutin on Src kinase blocks high glucose-induced EGFR/ERK transactivation in diabetic nephropathy by integrative approach of network pharmacology and experimental verification

BackgroundAlthough clinical strategies for diabetic nephropathy (DN) therapy include stringent blood pressure control through blockade of the renin-angiotensin system and management of hyperglycemia, the condition is still observed to progress relentlessly. PurposeTo elucidate the protective effects of rutin on podocytes in db/db mice with integrative approach of network pharmacology and experimental verification. MethodsThe study employs network pharmacology to identify common targets between rutin and DN, constructs a potential protein-protein interaction (PPI) network, and conducts Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking is utilized to evaluate the interaction between rutin and protein targets. Additionally, experimental validation is performed using db/db mice and human podocyte cell models. ResultsRutin has been found to have a significant renoprotective effect, reducing blood glucose, proteinuria, and improving renal function in db/db mice. Rutin's inhibition of Src kinase reduces the phosphorylation levels of EGFR and ERK, which may mitigate podocyte injury. Additionally, rutin exhibits antioxidant properties, capable of lowering the levels of reactive oxygen species (ROS) in kidney tissue and increasing the activity of antioxidant enzymes like superoxide dismutase (SOD). These effects help protect podocytes from oxidative stress, further supporting the potential application of rutin in the treatment of DN. ConclusionsThe inhibition of rutin on Src kinase blocks high glucose-induced EGFR/ERK transactivation and protects podocyte injury in DN, indicating it might serve as a promising therapeutic agent for podocyte-targeted therapies.

Simultaneous targeting and suppression of heat shock protein 60 to overcome heat resistance and induce mitochondrial death of tumor cells in photothermal immunotherapy

As the most aggressive and metastatic subtype of breast cancer, clinical demands of triple negative breast cancer (TNBC) have far not been met. Heat shock protein 60 (HSP60) is over expressed in tumor cells and impair the efficacy of photothermal therapy. In this work, a conjugate composed of self-designed peptide targeting HSP60 and gold nanorods was constructed, referred to as AuNR-P17. Results showed that AuNR-P17 was able to simultaneously down regulate the level of HSP60 and locate in the mitochondria where HSP60 is enriched in the tumor cells of TNBC, which also impeded the interaction between HSP60 and integrin α3, thereby reducing the tumor cells' heat tolerance and metastatic capabilities. At the same time, AuNR-P17 induced remarkable mitochondrial apoptosis when exposed to the laser irradiation of 808 nm. The dual functions of AuNR-P17 led to the decrement of BCL-2 and the activation of p53 and cleaved caspase-3. The danger associated molecular patterns (DAMPs) generated from the mitochondrial apoptosis elicited strong and long-term specific immune responses against TNBC in vivo and ultimately inhibited the tumor metastasis and recurrence with significantly prolonged survival (>100 days) on TNBC mice. In conclusion, this study demonstrated HSP60 a promising potential therapeutic target for triple negative breast cancer and exhibited powerful capacity of AuNR-P17 in photothermal immune therapy.

Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold

TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target.

Synthesis, structure, DFT study and molecular docking inspection of spirobi[hexahydropyrimidine]-diones derivative

It has been established that three-component condensation of benzaldehyde, acetone and urea catalyzed H2SO4 leads to the formation of spirobi[hexahidropyrimidine]-dione derivatives. The structure of the synthesized compound has been proved by X-ray method. The results of the quantum theory of atom-in-molecule and noncovalent interaction index analysis showed no intramolecular hydrogen bonds in the molecule studied. However, it contains four N-H bonds and two C=O groups. Based on the result of the DFT-NBO analysis, it was the lone pairs of oxygen on the C=O group which are forming strong orbital interactions with the antibonding orbital of the C-N single bond. The molecular docking was performed to investigate potential binding interactions of the compound with four target proteins including 5I4T (HIV-1), 5R7Z, 6M71 and 6VYB (SARS-Cov-2). Additionally, in-silico drug-likeness and ADME studies suggested oral activity (violations ≤ 1) of scaffold and predicted to be actively effluxed by P-gp (PGP+).

A multidomain PARP14 construct suitable for bacterial expression.

Poly-ADP-ribose polymerase-14 (PARP14) can modify proteins and nucleic acids by the reversible addition of a single ADP-ribose molecule. Aberrant PARP14 functions have been related to cancer and inflammation, and its domains are involved in processes related to viral infection. Previous research indicates that PARP14 functions might be mediated via a multitude of target proteins. In vitro studies of this large multidomain enzyme have been complicated by difficulties to obtain biochemical quantities of pure protein. Here we present a strategy that allows bacterial expression and purification of a functional multidomain construct of PARP14. We substituted an internal KH domain and its neighboring unstructured region with a SUMO domain to obtain a protein construct that encompasses three macrodomains, a WWE domain, and a PARP catalytic domain. We show that the resulting construct retains both ADP-ribosyltransferase and de-MARylase activities. This construct will be useful in structural and functional studies of PARP14.

Network Pharmacology Studies on the Molecular Mechanism of Hashimoto's Thyroiditis Treated with Shutiao Qiji Decoction.

In recent years, the number of patients with Hashimoto's thyroiditis has been increasing, and traditional Chinese medicine ingredients and combinations have been applied to treat Hashimoto's thyroiditis to increase efficacy and reduce side effects during the treatment process. Shutiao Qiji Decoction is one of the Chinese traditional medicine prescriptions, which is commonly used to treat cancer, tumor, etc. It is also used for thyroid-related diseases in the clinic. Hashimoto's thyroiditis is an autoimmune disease. In this study, the mechanism of Shutiao Qiji Decoction in treating Hashimoto's thyroiditis was studied through network pharmacology and molecular docking verification. Each Chinese medicine ingredient of Shutiao Qiji Decoction was retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The related genes of HT were searched from the UniProt and GeneCards databases. Meanwhile, we used Cytoscape to construct the protein-protein interaction (PPI) visual network analysis, and used the search tool to search the database of Interacting Genes (STRING) to build a PPI network. These key proteins were enriched and analyzed by molecular docking validation, Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Hashimoto's thyroiditis disease model was established in SD rats, and SQD was administered by gavage after the successful establishment of the model. After 6 weeks of continuous administration of the drug by gavage, tissue samples were collected and the thyroid and spleen tissues were visualized by HE staining to verify the therapeutic effect. The results showed that there were 287 TCM active ingredients, 1920 HT-related disease targets, and 176 drug and disease targets in SQD. Through PPI analysis, GP analysis, and KEGG analysis of the common targets of drugs and diseases, we found their pathways of action to be mainly cancer action pathway, PI3K-AKT signaling pathway, and T-cell action pathway. The active ingredients of the drugs in SQD, malvidin, stigmasterol, porin-5-en-3bta-ol, and chrysanthemum stigmasterol, were docked with the related target proteins, MAPK, GSK3β, TSHR, and NOTCH molecules. The best binding energies obtained from docking were mairin with TSHR, stigmasterol with TSHR, poriferast-5-en-3beta-ol with MAPK, and chryseriol with GSK3β, with binding energies of -6.84 kcal/mol, -6.53 kcal/mol, -5.03 kcal/mol, and -5.05 kcal/mol, respectively. HE staining sections of rat thyroid and spleen tissues showed that SQD had a therapeutic effect on Hashimoto's thyroiditis and restored its immune function. It is verified by molecular docking results that Shutiao Qiji Decoction has a potential therapeutic effect on Hashimoto's thyroiditis in the MAPK/TSHR/NOTCH signal pathway, and that the main components, mairin, stigmasterol, poriferast-5-en-3beta-ol, and chryseriol play a role in it. SQD has been shown to have a good therapeutic effect on Hashimoto's thyroiditis.

Design, Synthesis, and Evaluation of Antifungal Activity of Pyrazoleacetamide Derivatives.

Fungal infections have posed a big challenge in the management of their treatment. Due to the resistance and toxicity of existing drug molecules in the light of pandemic infections, like COVID-19, there is an urgent need to find newer derivatives of active molecules, which can be effective in fungal infections. In the present study, we aimed to design pyrazole derivatives using molecular modeling studies against target 1EA1 and synthesize 10 molecules of pyrazole derivatives using a multi-step synthesis approach. Designed pyrazole derivatives were synthesized by conventional organic methods. The newly synthesized pyrazole molecules were characterized by using FT-IR, 1HNMR, 13CNMR, and LC-MS techniques. Molecular docking studies were also performed. The antifungal activity of newly synthesized compounds was assessed in vitro against Candida albicans and Aspergillus niger using the well plate method. Two of the compounds, OK-7 and OK-8, have been found to show significant docking interaction with target protein 1EA1. These two compounds have also been found to show significant anti-fungal activity against Candida albicans and Aspergillus nigra when compared to the standard fluconazole. The Minimum Inhibitory Concentration (MIC) value of these two compounds has been found to be 50 μg/ml. Pyrazole derivatives with -CH3, CH3O-, and -CN groups have been found to be active against tested fungi and can be further explored for their potential as promising anti-fungal agents for applications in the field of medicinal chemistry.

Exploring the potential molecular targets of hydroxymethylbutyrate and glucosamine fortified whey protein drink to modulate sarcopenia and Alzheimer's disease by in silico and in vitro studies

Fortified foods have garnered significant attention as potential therapeutic strategies with less adverse effects and ready accessibility. However, precise formulation is required to optimize their beneficial effects. Our study aimed to unravel the mechanisms of a functional protein beverage, hydroxymethylbutyrate and glucosamine fortified whey protein drink (HG-WPD), as a possible intervention combatting sarcopenia and Alzheimer's disease (AD) by network pharmacology, molecular docking, and experimental assays. This study investigates the molecular pathways through which HG-WPD acts, by combining in silico and in vitro analyses. Our in silico study predicted the important target proteins, including acetylcholinesterase (AChE), matrix metalloproteinase 9 (MMP9), and angiotensin-converting enzyme (ACE), linked to both diseases. The molecular docking analysis showed that hydroxymethylbutyrate and glucosamine exhibited a notable binding affinity to these proteins, therefore suggesting their possible use as multi-target medicinal agents. In vitro studies on C2C12 myotubes showed that HG-WPD reduced dexamethasone-induced cell death highlighting its potential anti-sarcopenic actions. Furthermore, confirming their possible function in reducing cognitive impairment in AD, the antioxidant tests showed great activity of both substances. The results imply that HG-WPD is potentially effective for future therapeutic approaches as a functional food product with dual benefits in combatting sarcopenia and AD.

Network Pharmacology Prediction and Molecular Docking-based Strategy to Explore the Potential Mechanism of Guiyi Tonglong Prescription in the Treatment of Benign Prostatic Hyperplasia

Background: Benign prostatic hyperplasia (BPH) is a common condition affecting the urinary tract. This study aimed at exploring the potential of Guiyi Tonglong (GYTL) prescription for the treatment of benign prostatic hyperplasia using network pharmacology and molecular docking technology. Methods: The main active ingredients in GYTL prescription were identified from the Traditional Chinese Medicine Systems Pharmacology and the Integrative Pharmacology-based Traditional Chinese Medicine (TCMIP) databases based on drug similarity of ≥ 30% and oral bioavailability of ≥ 0.18. Protein–protein interaction (PPI) networks, gene ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to study the interactions and pathway enrichment and establish ingredient-target-pathway networks. The structure of the active ingredient was docked to that of the potential protein target using the AutoDock molecular docking software. Results: A total of 86 active ingredients and 130 potential targets were screened from GYTL prescription, and a PPI network was constructed to identify the five most important core targets, namely SRC, TP53, STAT3, AKT1, and PIK3CA. Enrichment analysis revealed that GYTL prescription may play a role in the treatment of BPH through multiple signaling pathways, such as PI3K-Akt, EGFR, AGE-RAGE, and HIF-1. Molecular docking indicated a potential interaction between the active ingredients and targets. Conclusion: These results provide further information regarding the active ingredients and molecular mechanisms of GYTL prescription in treating BPH.

Nutritional therapy among adult patients with severe burns: A retrospective observational study.

The objective of this study was to examine the effects of nutritional therapy in adult patients with severe burns. Sixty adult patients with severe burns were enrolled. Data on nutritional intake through enteral nutrition (EN) or parenteral nutrition (PN) on days 7, 14, 21, and 28 post-injury were collected. Patients were divided into target and non-target groups according to whether their energy or protein intake reached the target. Age, length of ventilation, and total bilirubin (TBIL), albumin (ALB), prealbumin (pALB), and C-reactive protein (CRP) concentrations of patients were recorded. The percentage of protein targets with protein delivery was lower than that of energy target with energy delivery. The ratio of PN protein to total protein was lower than that of PN energy to total energy on days 7, 14, 21, and 28 (p<0.001, p<0.001, p=0.001, and p=0.003, respectively). Compared to the non-target group on day 21, the target group was younger, had lower TBIL on day 7, higher ALB and pALB on day 21, and lower CRP on day 14 (p=0.025, p=0.021, p=0.028, p=0.029, and p=0.049, respectively). Multivariate logistic regression analysis showed that older age and longer ventilation were independent risk factors in patients who did not meet the nutritional target on day 21 (p=0.026 and p=0.043, respectively). The protein intake of adult patients with severe burns was low. Compared to the non-target group, the target group had better laboratory test results. Older age and longer ventilation were independent risk factors for patients not meeting the nutritional target.