Network pharmacology and molecular docking reveal the mechanism of resveratrol in oral squamous cell carcinoma treatment / 口腔疾病防治

Objective@#To explore the molecular mechanism of resveratrol (RES) in the treatment of oral squamous cell carcinoma (OSCC) through the use of biological information methods such as network pharmacology and molecular docking and to provide a theoretical reference for the clinical application of RES in the treatment of OSCC.@*Methods@#The Swiss Target Prediction(http://www.swisstargetprediction.ch), SEA (http://sea.bkslab.org)database, and Pharm mapper database(http://lilab-ecust.cn) were used to retrieve RES-related targets, and the DISGENET (www.disgenet.org), OMIM (https://omim.org) and GeneCards (https://www.genecards.org) databases were used to screen OSCC disease targets. The intersection of drugs and disease targets was determined, and Cytoscape 3.7.2 software was used to construct a "drug-diseasetarget pathway" network. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to construct a target protein interaction network, and the DAVID database was used for enrichment analysis of key proteins. Finally, molecular docking validation of key proteins was performed using AutoDock and PyMOL. The enrichment analysis and molecular docking results were integrated to predict the possible molecular mechanisms of RES treatment in OSCC; western blot was used to determine the effect of resveratrol at different concentrations (50, 100) μmol/L on the expression of Src tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), estrogen receptor gene 1 (ESR1), and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway proteins in OSCC HSC-3 cells.@*Results@#A total of 243 targets of RES drugs and 6 094 targets of OSCC were identified. A total of 116 potential common targets were obtained by intersecting drugs with disease targets. These potential targets mainly participate in biological processes such as in vivo protein self-phosphorylation, peptide tyrosine phosphorylation, transmembrane receptor protein tyrosine kinase signaling pathway, and positive regulation of RNA polymerase Ⅱ promoter transcription, and they interfere with the PI3K/AKT signaling pathway to exert anti-OSCC effects. The docking results of resveratrol with OSCC molecules indicated that key targets, such as EGFR, ESR1, and SRC, have good binding activity. The results of cell-based experiments showed that resveratrol inhibited the protein expression of SRC, EGFR, ESR1, p-PI3K, and p-AKT in HSC-3 cells in a dose-dependent manner.@*Conclusion@#RES can inhibit the expression of its targets EGFR, ESR1, SRC, p-PI3K, and p-AKT in OSCC cells.

Caries prevention mechanism of the Xinjiang Mori Cortex based on network pharmacology and its effect on the main cariogenic bacteria / 口腔疾病防治

Objective@#To investigate the potential caries prevention mechanism of the Xinjiang Mori cortex and to analyze its effect on the main cariogenic bacteria.@*Methods@#The active components of the Xinjiang Mori cortex and the main targets were predicted and screened using the TCMSP database. The GeneCards, DisGENET and TTD databases were used to obtain caries-related targets. The common targets were derived, and core genes were screened. The enrichment analysis was performed using the DAVID data platform. Molecular docking was performed using AutoDock software. In in vitro antibacterial experiments, first, the 50% minimum inhibitory concentration (MIC50) and the minimum bactericidal concentration (MBC) of the Xinjiang Mori Cortex extract against Streptococcus mutans, Streptococcus sanguis and Actinomyces viscosus were determined and the growth curves were measured. The effects of the Xinjiang Mori Cortex extract on acid production, polysaccharide production and adhesion ability of Streptococcus mutans, Streptococcus sanguis and Actinomyces viscosus in the planktonic state were determined. The 50% minimum biofilm inhibition concentration (MBIC50) and 50% minimum biofilm reduction concentration (MBRC50) were determined by crystal violet staining, and biofilm morphology was visualized using scanning electron microscopy (SEM).@*Results@#The main active components of the Xinjiang Mori cortex included quercetin, kaempferol, and β-sitosterol. Tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1beta (IL-1β) could be the most important targets of the Xinjiang Mori cortex for the prevention of dental caries. The enrichment analysis results showed that Mori cortex extract may have effects on the AGE-RAGE signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. The antibacterial experiment results showed that the MIC50 values of Xinjiang Mori Cortex extract against Streptococcus mutans, Streptococcus sanguis and Actinomyces viscosus were 0.5, 0.5 and 0.25 mg/mL, respectively, and the MBCs were 4.0, 2.0 and 1.0 mg/mL, respectively. The inhibitory effect of Xinjiang Mori Cortex extract on the acid production, polysaccharide production and adhesion ability of three major cariogenic bacteria in the planktonic state was stronger than that of the control group, and the differences were statistically significant (P<0.05). The MBIC50 was 1.0, 1.0, and 0.5 mg/mL, and the MBRC50 was 4.0, 4.0, and 2.0 mg/mL. SEM observation showed that the amount of biofilm formation decreased with the drug concentration compared with the control group.@*Conclusion@#Xinjiang Mori cortex extract can prevent caries through quercetin, kaempferol, and β-sitosterol active ingredients, TNF、IL-6、IL-1β key targets and multiple pathways and inhibit the growth, acid production, polysaccharide production, and adhesion ability of three major cariogenic bacteria in the planktonic state and has some inhibitory effect on corticogenic biofilm formation.

Mechanism of Qizhenziyin mixture in the treatment of hypogonadism based on network pharmacology analysis and molecular docking / 药学实践杂志

Objective To investigate the mechanism of Qizhenziyin mixture in the treatment of hypogonadism by using the network pharmacology approach. Methods The active components of Qizhenziyin mixture were obtained by searching TCMSP ，TCMID and HIT databases.The related targets of candidate compounds were obtained by searching STITCH databases. The potential targets of Qizhenziyin mixture in the treatment of hypogonadism were obtained by mapping the disease genes of hypogonadism with Genecards and DisGeNet databases. The protein interaction platform database (STRING) was used to construct the interaction relationship between action targets. The target protein interaction （PPI） network was constructed by introducing Cytoscape software. The mechanism of Qizhenziyin mixture in the treatment of hypogonadism was explained through the enrichment analysis of GO, KEGG and molecular docking technology. Results A total of 148 drug-disease chemical compounds, 96 drug-disease intersection targets, 1085 disease targets were obtained；the components for treating diseases are: quercetin，kaempferol, luteolin, etc; enrichment analysis of GO revealed 1792 biological processes （BP）, 31 cellular components (CC) and 79 molecular functions (MF)；the results of KEGG pathway enrichment analysis indicated such as FOXO signaling pathway, prostate cancer, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, etc.The results of molecular docking showed that kaempferol and LEP had the best and stable binding energy. Conclusion The active components of Qizhenziyin mixture may play a role of the treatment of hypogonadism by improving insulin resistance and the expression of testosterone synthetase of Leydig cells.

Rational drug repurposing for alzheimer's treatment using in-silico ligand and structure-based approaches

Abstract Alzheimer's disease is a devastating neurodegenerative disorder characterized by memory loss and cognitive decline. New AD treatments are essential, and drug repositioning is a promising approach. In this study, we combined ligand-based and structure-based approaches to identify potential candidates among FDA-approved drugs for AD treatment. We used the human acetylcholinesterase receptor structure (PDB ID: 4EY7) and applied Rapid Overlay of Chemical Structures and Swiss Similarity for ligand-based screening.Computational shape-based screening revealed 20 out of 760 FDA approved drugs with promising structural similarity to Donepezil, an AD treatment AChE inhibitor and query molecule. The screened hits were further analyzed using docking analysis with Autodock Vina and Schrodinger glide. Predicted binding affinities of hits to AChE receptor guided prioritization of potential drug candidates. Doxazosin, Oxypertine, Cyclopenthiazide, Mestranol, and Terazosin exhibited favorable properties in shape similarity, docking energy, and molecular dynamics stability.Molecular dynamics simulations confirmed the stability of the complexes over 100 ns. Binding free energy analysis using MM-GBSA indicated favourable binding energies for the selected drugs. ADME, formulation studies offered insights into therapeutic applications and predicted toxicity.This comprehensive computational approach identified potential FDA-approved drugs (especially Doxazosin) as candidates for repurposing in AD treatment, warranting further investigation and clinical assessment.

Anthropometry of deep-set eyes with respect to difficulty in docking during femtosecond laser procedures

Purpose: To identify the facial anthropometric parameters that predict the difficulty during femtosecond (FS) laser. Methods: This was a single?center observational study was conducted on participants between the ages 18 and 30 years who were planned for FS?LASIK (femtosecond laser?assisted laser in situ keratomileusis) or SMILE (small incision lenticule extraction) at Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India. The front and side?facing images of the participants were analyzed using Image J software to measure different anthropometric parameters. The nasal bridge index, facial convexity, and other parameters were measured. The difficulty faced by the surgeon during docking was recorded for each subject. The data were analyzed on Stata 14. Results: A total of 97 subjects were included. The mean age was 24 (±7) years. Twenty?three (23.71%) subjects were females while the rest were males. Difficulty in docking was seen in 1 (4.34%) female and 14 (19%) males. The mean nasal bridge index was 92.58 (±4.01) in subjects with deep?set eyes and 89.72 (±4.30) in normal subjects. The mean total facial convexity was 129.28 (±4.24) in deep?set eyes, and 140.23 (±4.74) in normal subjects. Conclusion: Total facial convexity appeared as the most important feature, with the value being less than 133° in most subjects with unfavorable facial anthropometry

In Silico Investigation of Phytochemicals against Typhoid: A Review

Typhoid fever is a serious bacterial infection caused by Salmonella enterica serovar Typhi, and is a major public health issue in developing countries. The emergence of multidrug-resistant strains of S. Typhi has raised concerns about the effectiveness of existing treatments and has prompted the exploration of alternative therapies. Phytochemicals, which are bioactive compounds found in plants, have been investigated as potential sources of new antibacterial agents against typhoid. In this review, we conducted an in silico investigation of phytochemicals and their potential activity against S. Typhi. Our review examined current literature on phytochemicals and their antibacterial activity against S. Typhi. Using molecular docking studies, we investigated the potential binding of these phytochemicals to the target protein, DNA gyrase, which is an important drug target in S. Typhi. Our results indicate that several phytochemicals exhibit promising binding affinities to DNA gyrase, suggesting their potential as effective antibacterial agents against typhoid. Overall, our findings highlight the potential of phytochemicals as a source of new therapeutics for typhoid fever, particularly in regions where multidrug-resistant strains of S. Typhi are prevalent. The in silico approach used in this review provides a valuable tool for screening and identifying potential candidates for further investigation. Further studies are needed to validate the results of in silico studies and to explore the potential of phytochemicals as antibacterial agents against typhoid.

Binding interaction of laccases from Bacillus Subtilis after industrial dyes exposure: Molecular docking and molecular dynamics simulation studies

Dyes are becoming more widely used around the world wide, but there is no effective bioremediation approach for removing them completely from the environment. Several dyes are mentioned to be degraded through bacteria; however, it's still unknown how the particular enzymes act throughout the dye degradation. The behavior and function of these enzymes in the biodegradation of azo dyes (Textile dyes) had been investigated experimentally by the numbers of the researchers, however, the molecular mechanisms remain unclear. Therefore, the interaction mechanisms of textile dye (methyl orange) with laccase from B. subtilis were explored through molecular docking and molecular dynamics simulations, the three selected dyes (methyl orange, malachite green, and acid blue 62) that interact positively with laccase on the basis of their maximum binding energy, molecular docking results indicate that one of the three dyes is more stable as a target for degradation through Bacillus subtilis laccase. Therefore, subsequent research focused solely on one substrate: methyl orange. Molecular Dynamics simulation study was applied after the molecular docking to determine the interaction between laccases and methyl orange dyes. The trajectory was proved with root mean square deviation and root mean square fluctuation analysis. According to the molecular dynamics simulation results, laccase-methyl orange complexes remain stable during the catalytic reaction. So, this study demonstrates how laccase is involved in methyl orange bioremediation.

Repositioning of FDA-approved drugs for the treatment of methicillin-resistant Staphylococcus aureus infection: Structure-based virtual screening and in vitro assay

Background: Computer-aided repositioning of approved drugs is an increasingly popular strategy for the discovery of effective therapies. The potency of the newly repositioned drugs can be optimized using them as a component of an effective drug combination, thereby achieving the desired therapeutic effect at a lower and more tolerable drug concentration. Aim and Objectives: The aim of the study was to perform structure-based virtual screening and repurposing of FDA-approved drugs for the treatment of methicillin resistance by Staphylococcus aureus (SA) and perform an in vitro validation of the prediction. Materials and Methods: Following ethical clearance at the Department of Pharmacology and Therapeutics, College of Health Sciences, Usmanu Danfodiyo University Sokoto, molecular docking was performed against 5 validated protein targets involved in the development of methicillin resistance by SA and an in vitro validation of the prediction was done using 3 of the top-ranking drug candidates against methicillin-resistant vancomycin-susceptible strain of the pathogen (ATCC 43300). Results: Desmopressin and docetaxel, two of the 20 top-ranking repurposed drugs discovered through virtual screening, enhanced the inhibitory effect of oxacillin against the ATCC 43300 SA strain in a ratio-dependent manner, although each of the two drugs singly was only weakly effective against the bacterial strain. The standard drug, vancomycin (also among the top-scoring candidates), alone, was effective against ATCC 43300 strain and in combination with oxacillin, the two drugs produced a ratio-dependent synergistic effect against the bacterial strain. Conclusion: These findings suggest that oxacillin-based combinations with desmopressin, docetaxel, and the standard drug vancomycin, three of the 20 top-ranking drugs, at optimum ratios, may be beneficial in reversing the resistance of the ATCC 43300 SA strain to oxacillin, thus supporting the prediction of the molecular docking results.

Estudio computacional de las interacciones moleculares entre el timol y los residuos HIS41 y CYS145 presentes en el sitio activo de la proteasa 3CLpro

La proteína proteasa 3CLpro del SARS-CoV-2 es una enzima crucial para la replicación viral, razón por la cual se convierte en un blanco terapéutico de gran importancia. El timol (2-isopropil-5-me-tilfenol), un compuesto natural que se encuentra en el tomillo (Thymus vulgaris), exhibe potencial actividad antiviral contra la proteasa 3CLpro. En este estudio, usando acoplamiento molecular con AutoDockTools-1.5.6, se evaluaron las energías de interacción molecular entre el timol y los residuos de aminoácidos en el sitio activo de la proteína proteasa 3CLpro. Luego, con la teoría cuántica de Átomos en Moléculas (QTAIM) y la de Interacciones no covalentes (NCI) se analizaron los tipos de interacciones moleculares entre los residuos de aminoácidos identificados y el timol. Los cálculos cuánticos se llevaron con el software Orca-5.0.3, utilizando el método DFT con el funcional M06-2X y el conjunto base aug-cc-pVDZ en fase gaseosa. Los resultados de acoplamiento molecular indican que el timol se une a la proteína 3CL con una energía de interacción igual a -3,784 kcal/mol. El análisis QTAIM indica la presencia de puntos críticos de enlace entre el timol y los residuos HIS41 y CYS145. Además, se observa la formación de un enlace de hidrógeno entre el grupo OH del timol y el residuo CYS145, lo cual es corroborado por los análisis ELF (Electron Localization Function) y NCI (Non Covalent Interactions). Finalmente, el método NCI confirma la presencia de interacciones de Van der Waals con el residuo HIS41. Los resultados sugieren que el mecanismo de inhibición de la actividad de la proteína 3CLpro es controlado por interacciones moleculares tipo puente de hidrógeno e interacciones débiles.

The protease 3CLpro of the SARS-CoV-2 is a crucial enzyme for viral replication, becoming a highly important therapeutic target. Thymol (2-isopropyl-5-methyl-phenol), a naturally occurring compound found in thyme, exhibits potential antiviral activity against the 3CLpro protease. In this study, using molecular docking with AutoDockTools-1.5.6, the molecular interaction energies between thymol and amino acid residues in the active site of the protein protease 3CLpro were evaluated. Then, with the Atoms in Molecules (QTAIM) and Non-covalent Interactions (NCI) theories, the types of molecular interactions between identified amino acid residues and thymol were analyzed. Quantum calculations were carried out with the Orca-5.0.3 software using the DFT method with the M06-2X functional and the aug-cc-pVDZ basis set in the gas phase. The molecular docking results indicate that thymol is linked to the 3CL protein with an interaction energy equal to -3.784 kcal/mol. QTAIM analysis indicates the presence of critical binding sites between thymol and residues HIS41 and CYS145. In addition, the formation of a hydrogen bond between the OH group of thymol and the CYS145 residue is observed, which is corroborated by the ELF and NCI analyses. Finally, the NCI method confirms the presence of Van der Waals interactions with the HIS41 residue. The results suggest that the mechanism of inhibition of the activity of the 3CLpro protein is controlled by molecular interactions such as hydrogen bonding and weak interactions.

A protease 3CLpro do SARS-CoV-2 é uma enzima crucial para a replicação viral, tornando-se um alvo terapêutico de grande importÅncia. O timol (2-isopropil-5-me-tilfenol), um composto natural encontrado no tomilho, exibe potencial atividade antiviral contra a protease 3CLpro. Neste estudo, utilizando o docking molecular com o AutoDockTools-1.5.6, foram avaliadas as energias de interação molecular entre o timol e os residuos de aminoácidos no sítio ativo da proteína protease 3CLpro. Em seguida, com a teoria quantica de atomos em moleculas (QTAIM) e da interacões no-covalentes (NCI), foram analisados os tipos de interações moleculares entre os resíduos de aminoácidos identificados e o timol. Os cálculos quÅnticos foram realizados com o software Orca-5.0.3 usando o método DFT com o funcional M06-2X e a base aug-cc-pVDZ definida na fase gasosa. Os resultados do docking molecular indicam que o ti-mol está ligado à proteína 3CL com uma energia de interação igual a -3.784 kcal/ mol. A análise QTAIM indica a presença de sítios de ligação críticos entre o timol e os resíduos HIS41 e CYS145. Além disso, observa-se a formação de uma ponte de hidrogênio entre o grupo OH do timol e o resíduo CYS145, o que é corroborado pelas análises ELF e NCI. Finalmente, o método NCI confirma a presença das interações de Van der Waals com o resíduo HIS41. Os resultados sugerem que o mecanismo de inibição da atividade da proteína 3CLpro é controlado por interações moleculares como ligações de hidrogênio e interações fracas.

Design, synthesis, characterization and in vitro evaluation of some novel thiol-substituted 1,3,4-oxadiazoles as GlmS inhibitors

The development of novel medications with previously unidentified action mechanisms is required due to the increasing in antibiotic resistance amongst dangerous microbes. The major goal of the research was to develop in silico and in vitro antibacterial methods for designing an active thiol substituted oxadiazole inhibitor targeting gram-negative and gram-positive bacteria's GlmS receptor. 1,3,4-Oxadiazole was proposed as a scaffold, and the possibility of its synthesis was examined. The least amount of free energy in the ligand configurations was chosen. Analyses of the novel molecules' characteristics were done using ADMET studies. There were four distinct reactions used in the synthesis processes. As the first reagent, substituted carboxylic acids were utilized. Synthesized compounds were characterized by spectral studies and minimum inhibitory concentration was evaluated by in vitro antibacterial examinations of synthesized compounds. Ciprofloxacin served as the study's reference drug. Based on in vitro studies and in silico molecular docking, ROS1-4 established strong binding energy, while ROS3 revealed significant antibacterial activity. These findings support the hypothesis that the proposed scaffold significantly inhibits the GlmS receptor protein.

Network pharmacology and molecular docking study of the active ingredients in Saptasaram kashayam for the treatment of Polycystic ovary syndrome-Supplemenntary data

Polycystic Ovary Syndrome (PCOS) is one of the most prevalent endocrine disorder in women of reproductive age characterized by hyperandrogenism (HA). Current treatment options for PCOS are either with adverse effects or ineffective. Saptasaram kashayam (SK), an ayurvedic formulation is often been a safe traditional alternative medicine to improve the PCOS symptoms as well as its pathological development. However, its principle phytoconstituents or underlying mechanisms have not been investigated. In order to achieve this, the current study systematically utilized computational tools, network pharmacology approaches and molecular docking studies. All identified phytoconstituents of SK were screened by QikProp ADME prediction and 47 were selected based on oral bioavailability and drug likeliness scores. Their 3D structures were submitted to three online target fishing webservers PharmMapper, ChemMapper and Swiss Target Prediction which produced 1084 biological targets for SK comprehensively. 350 known PCOS therapeutic targets were retreived as common targets from three different interrogative disease centric bioinformatic platforms DisGeNET, OMIM and GeneCards. Intersection of 1084 biological targets of SK and 350 PCOS therapeutic targets produced, 88 potential therapeutic targets of SK against PCOS. STRING PPI and Compound-Target-Pathway networks were constructed and analysed using Cytoscape software. GO & KEGG pathway enrichment analysis was performed using DAVID database. 15 PCOS therapeutic target proteins were short listed from network analysis report- PIK3CA, PDPK1, AKT1, PIK3R1, STAT3, MAPK1, MAPK3, EGFR, AR, ESR1, ESR2, SHGB, NOS3, F2 & CREBBP. Targets that were likely to be inhibited/modulated by SK for treatment of PCOS were docked against the screened phytoconstituents and their respective standard inhibitors using GLIDE-SP of Schrodinger suite, Maestro version- 13.0. Results showed that Quercetin, Catechin, Boeravinone J, Genistein, Protocatechuic Acid, Gentisic Acid, Xanthoarnol, Luteolin, Boeravinone F, Tyrosine, Kaempferol, Dalbergioidin, etc exhibited good binding affinities when compared to standard drugs and might be responsible for synergistic/additive protective effect of SK against PCOS. Meanwhile PI3K-Akt signaling pathway, Prolactin signaling pathway, AGE-RAG diabetic complications, HIF-1 signaling pathway and Estrogen signaling pathway were found to be involving the hub genes of interest and in this way, they might be intervened during treatment of PCOS by SK. Present study succeeded in identifying the drug like principle phytoconstituents, probable PCOS therapeutic targets and the underlying molecular mechanism of SK apart from providing reliable evidence for therapeutic potential of SK against PCOS. However further validation by in vitro and in vivo investigations is necessary.

Network pharmacology and molecular docking study of the active ingredients in Saptasaram kashayam for the treatment of Polycystic ovary syndrome

Polycystic Ovary Syndrome (PCOS) is one of the most prevalent endocrine disorder in women of reproductive age characterized by hyperandrogenism (HA). Current treatment options for PCOS are either with adverse effects or ineffective. Saptasaram kashayam (SK), an ayurvedic formulation is often been a safe traditional alternative medicine to improve the PCOS symptoms as well as its pathological development. However, its principle phytoconstituents or underlying mechanisms have not been investigated. In order to achieve this, the current study systematically utilized computational tools, network pharmacology approaches and molecular docking studies. All identified phytoconstituents of SK were screened by QikProp ADME prediction and 47 were selected based on oral bioavailability and drug likeliness scores. Their 3D structures were submitted to three online target fishing webservers PharmMapper, ChemMapper and Swiss Target Prediction which produced 1084 biological targets for SK comprehensively. 350 known PCOS therapeutic targets were retreived as common targets from three different interrogative disease centric bioinformatic platforms DisGeNET, OMIM and GeneCards. Intersection of 1084 biological targets of SK and 350 PCOS therapeutic targets produced, 88 potential therapeutic targets of SK against PCOS. STRING PPI and Compound-Target-Pathway networks were constructed and analysed using Cytoscape software. GO & KEGG pathway enrichment analysis was performed using DAVID database. 15 PCOS therapeutic target proteins were short listed from network analysis report- PIK3CA, PDPK1, AKT1, PIK3R1, STAT3, MAPK1, MAPK3, EGFR, AR, ESR1, ESR2, SHGB, NOS3, F2 & CREBBP. Targets that were likely to be inhibited/modulated by SK for treatment of PCOS were docked against the screened phytoconstituents and their respective standard inhibitors using GLIDE-SP of Schrodinger suite, Maestro version- 13.0. Results showed that Quercetin, Catechin, Boeravinone J, Genistein, Protocatechuic Acid, Gentisic Acid, Xanthoarnol, Luteolin, Boeravinone F, Tyrosine, Kaempferol, Dalbergioidin, etc exhibited good binding affinities when compared to standard drugs and might be responsible for synergistic/additive protective effect of SK against PCOS. Meanwhile PI3K-Akt signaling pathway, Prolactin signaling pathway, AGE-RAG diabetic complications, HIF-1 signaling pathway and Estrogen signaling pathway were found to be involving the hub genes of interest and in this way, they might be intervened during treatment of PCOS by SK. Present study succeeded in identifying the drug like principle phytoconstituents, probable PCOS therapeutic targets and the underlying molecular mechanism of SK apart from providing reliable evidence for therapeutic potential of SK against PCOS. However further validation by in vitro and in vivo investigations is necessary.

A comparative computational approach on the most deleterious missense variant in Connexin 43 protein and its potent inhibitor analysis

Intercellular communication between the cell plays an essential role in cell growth and cell formation, including migration, metabolism, and cell differentiation. Cell function and tissue homeostasis are maintained through gap junction intercellular communication (GJIC), thus regulating connexin hemichannels. Mis regulation of such connexin, especially connexin (Cx) 43, affects a comprehensive process, including cell differentiation, inflammation, and cell death. Mis regulation may be due to the missense variant in Cx43. Thus, we screened the complete set of mutations from public mutational databases and obtained 219 missense variants, which were then classified based on their pathogenicity, functional impact, stability, conservation, and physiochemical properties. Variant L214P was scrutinized to have the most deleterious, which was then modelled using the I-TASSER server and performed molecular docking analysis to screen potent inhibitors. The compound Kanamycin, Ginsenoside, and Astragaloside IV have better interactions with Cx43 mutant with a maximum of 5 hydrogen bonds. Ginsenoside is a compound that follows a Lipinski rule of five. Thus, the result obtained from this study suggests that Ginsenoside would be a better potent inhibitor for native and mutant Cx43.

Mannich bases derivatives of 2-Phenyl-5-Benzimidazole sulfonic acid; Synthesis, Characterization, Computational studies and Biological evaluation

Abstract A new series of N-Mannich bases of 2-Phenyl-5-benzimidazole sulfonic acid have been synthesized through amino methylation reaction with secondary amines. The two moieties were held together through a methylene bridge, which comes from formaldehyde (Formalin Solution 37%) used in the reaction. Chemical structures of the newly synthesized compounds have been confirmed using FT-IR, 1HNMR and 13CNMR. Different in vitro assays including Anti-oxidant, Enzyme inhibition, Anti-microbial and Cytotoxicity assay were performed to evaluate the biological potential with reference to the standard drug. Among the synthesized library, compound 3a shows maximum alpha-glucosidase inhibition with an IC50 value of 66.66 µg/ml, compound 3d was found most toxic with LC50 value of 10.17 µg/ml. ADME evaluation studies were performed with the help of Molinspiration online software. Docking calculations were also performed. Given the importance of the nucleus involved, the synthesized compound might find extensive medicinal applications as reported in the literature.

Investigations on the cytotoxicity and antimicrobial activities of terezine E and 14-hydroxyterezine D

Secondary metabolites produced by endophytes are an excellent source of biologically active compounds. The newly isolated natural products terezine E and 14-hydroxyterezine D are endophytic metabolites exhibiting anticancer activity recently identified by our team (https://doi.org/10.1080/14786419.2018.1489393). In our current study, we evaluated their affinity for binding to the active site of histone deacetylase (PDB ID: 4CBT) and matrix metalloproteinase 9 (PDB ID: 4H3X) by molecular docking using AutoDock Vina software after having tested their cytotoxic activities on three cell lines (human ductal breast epithelial tumor cells (T47D)-HCC1937), human hepatocarcinoma cell line (HepG2)-HB8065), and human colorectal carcinoma cells (HCT-116)-TCP1006, purchased from ATCC, USA)). Additionally, their antimicrobial activities were investigated, and their minimum inhibitory concentration (MIC) values were determined against P. notatum and S. aureus by the broth microdilution method. Higher cytotoxicity was observed for terezine E against all tested cell lines compared to 14-hydroxyterezine D. Molecular docking results supported the high cytotoxicity of terezine E and showed higher binding affinity with 4CBT with an energy score of 9 kcal/mol. Terezine E showed higher antibacterial and antifungal activities than 14-hydroxyrerezine D: MIC values were 15.45 and 21.73 µg/mL against S. aureus and 8.61 and 11.54 µg/mL against P. notatum, respectively.

Determinação da atividade antitirosinase e antioxidante de Myrsine coriacea (Sw. ) R. Br. ex Roem. & Schult. (Primulaceae) / Determination of the antityrosinase and antioxidant activity of Myrsine coriacea (Sw. ) R. Br. ex Roem. & Schult. (Primulaceae)

myrsine coriacea (Sw.) R. Br. ex Roem. & Schult. (Primulaceae) conhecida popularmente como capororoquinha ou capororoca, é amplamente distribuída nas regiões sul e sudeste do Brasil. As espécies desse gênero apresentam um potencial antioxidante e anti-inflamatório, que pode ser acessado na busca de novos ativos para o tratamento de desordens pigmentares da pele. Desta forma, este trabalho teve como objetivos avaliar o potencial antitirosinase e antioxidante de extratos e frações de M. coriacea e identificar os possíveis compostos responsáveis por essas atividades. Foram realizados ensaios para avaliar o potencial antioxidante das amostras através do método do DPPH, enquanto a capacidade hipopigmentante das amostras foi avaliado pela inibição da enzima tirosinase. Como complemento, foram determinados os teores de compostos fenólicos totais e flavonoides através dos métodos colorimétricos empregando o reagente Folin-Ciocalteau e AlCl3. Adicionalmente, os extratos de M. coriacea tiveram avaliados seus potenciais citotóxicos utilizando diferentes linhagens tumorais humanas. O perfil fitoquímico de M. coriacea foi analisado por cromatografia a gás acoplada com espectrometria de massas (CG-EM) e cromatografia em camada delgada (CCD) com padrões. Nessas análises foram identificados 34 compostos, sendo o ácido palmítico e o palmitato de etila os compostos majoritários nas amostras de M. coriacea. O extrato bruto das folhas apresentou o maior teor de fenólicos totais, enquanto a fração de acetato de etila das folhas teve o maior teor de flavonoides. Contudo, o extrato bruto dos frutos apresentou a melhor atividade antioxidante de todas as amostras analisadas, apresentando também a melhor atividade antitirosinase. Dentre os compostos anotados, mandenol, ácido -linoleico e o linolenato de etila foram os compostos considerados como possíveis inibidores da tirosinase, com boa interação molecular com a enzima nas análises de ancoragem molecular in silico. Das amostras analisadas com relação a inibição de crescimento frente as células tumorais, a amostra da fração de clorofórmio das folhas foi a que apresentou potencial antitumoral frente as células de adenocarcinoma de cólon (HCT116)

myrsine coriacea (Sw.) R. Br. ex Roem. & Schult. (Primulaceae) popularly known as capororoquinha or capororoca, is widely distributed in southern and southeastern Brazil. Myrsine species have an antioxidant and anti-inflammatory potential, which can be accessed in the search for new actives for the treatment of skin pigmentation disorders. Thus, this work aimed to evaluate the antityrosinase and antioxidant potential from extracts and fractions of M. coriacea and to identify the probable compounds responsible for these activities. Assays were performed to evaluate the antioxidant potential of the samples using the DPPH method, while the hypopigmentation capacity of the samples was evaluated by the tyrosinase inhibition. As a complement, the amounts of total phenolic compounds and flavonoids were determined through colorimetric methods using the Folin-Ciocalteau reagent and AlCl3. Additionally, M. coriacea extracts had their cytotoxic potential evaluated using different human tumor cell lines. M. coriacea phytochemical profile was obtained by gas chromatography coupled with mass spectrometry (GC-MS) and thin layer chromatography (TLC) with standards. In these analyses, 34 compounds were identified, with palmitic acid and ethyl palmitate as the major compounds in M. coriacea samples. The leaf crude extract presented the highest total phenolics contents, while the leaf ethyl acetate fraction had the highest flavonoid amounts. However, the fruit crude extract showed the best antioxidant and antityrosinase activities of all analyzed samples. Among the annotated compounds, mandenol, -linoleic acid and ethyl linolenate were the compounds considered as putative tyrosinase inhibitors, presenting good molecular interaction with the enzyme active site in the in silico molecular docking analysis. The leaf chloroform fraction was the only sample that showed an antitumor potential against colon adenocarcinoma cells (HCT116)

Fosfatase Cdc25B: Interações transientes intramoleculares e complexação com pequenos ligantes / Cdc25B phosphatase: Transient intramolecular interactions and small molecules complexation

Proteínas tirosina-fosfatase (PTPs) possuem papel fundamental na regulação da transdução de sinais e estão envolvidas em diversos processos fundamentais do ciclo celular. As Cdc25 (Cell Division Cycle 25) são fosfatases duais encontradas em todos os organismos eucarióticos e atuam em checkpoints do ciclo celular, permitindo ou inibindo o prosseguimento deste. Este grupo de proteínas pertence à classe de PTPs com atividade baseada em cisteína, apresenta domínio catalítico altamente conservado assim como o motivo catalítico, P-loop. Devido sua função, as Cdc25 são consideradas possíveis alvos terapêuticos para tratamento de câncer e sua interação com pequenas moléculas e inibidores tem sido investigada de forma que análises estruturais e de ligação das Cdc25 com inibidores podem elucidar aspectos importantes do mecanismo de ação destes além de direcionar para o desenho racional de fármacos. Interações cátion-π são interações intra ou intermoleculares não-covalentes que ocorrem entre uma espécie química catiônica, como o grupo guanidino de argininas, e uma das faces de um sistema π rico em elétrons, como dos anéis indólicos de triptofanos. Apesar de pouco discutidas na literatura, quando em comparação às interações não-covalentes mais convencionais, do ponto de vista energético as interações cátion-π são tão importantes na estruturação de proteínas quanto às ligações de hidrogênio ou pontes salinas. De fato estas interações são observadas com frequência em estruturas proteicas resolvidas. O domínio catalítico da Cdc25B possui diversas argininas expostas em sua superfície e um único resíduo de triptofano localizado na região C-terminal flexível, muito próximo do sítio catalítico da proteína. A flexibilidade de proteínas ou de regiões proteicas apresenta importante papel no reconhecimento entre biomoléculas participantes de vias de sinalização e tem sido muito estudada atualmente. Aqui, simulações de dinâmica molecular, experimentos de 1H-15N HSQC RMN, ensaios de cinética de inibição e de ancoragem molecular, evidenciam a existência de contatos cátion-π transientes na superfície de um importante membro da família das Cdc25, a Cdc25B, e de sítios de interação entre inibidores testados e a proteína com destaque a sítios na proximidades do P-loop, região próxima ao C-terminal desordenado, onde se demonstra estabilidade da interação com os pequenos ligantes

Protein tyrosine phosphatase (PTPs) play a fundamental role in the regulation of signal transduction and are involved in several fundamental processes of the cell cycle. Cdc25 (Cell Division Cycle 25) are dual phosphatases found in all eukaryotic organisms and act at checkpoints of the cell cycle, allowing or inhibiting its progression. This group of proteins belongs to the class of PTPs with cysteine-based activity, presenting a highly conserved catalytic domain as well as the catalytic motif, P-loop. Due to their function, Cdc25 are considered possible therapeutic targets for cancer treatment and their interaction with small molecules and inhibitors has been investigated so that structural and binding analyzes of Cdc25 with inhibitors can elucidate important aspects of their mechanism of action besides directing to rational drug design. Cation-π interactions are non-covalent intra- or intermolecular interactions that occur between a cationic chemical species, such as the guanidino group of arginines, and one of the faces of an electron-rich system, such as the indole rings of tryptophans. Although little discussed in the literature, when compared to more conventional non-covalent interactions, from the energetic point of view, cation-π interactions are as important in the structuring of proteins as hydrogen bonds or salt bridges. In fact, these interactions are frequently observed in solved protein structures. The catalytic domain of Cdc25B has several arginines exposed on its surface and a single tryptophan residue located in the flexible C-terminal region, very close to the catalytic site of the protein. The flexibility of proteins or protein regions plays an important role in the recognition between biomolecules participating in signaling pathways and has been extensively studied today. Here, molecular dynamics simulations, 1H-15N HSQC NMR experiments, inhibition kinetics and molecular anchoring assays, evidence the existence of transient cation-π contacts on the surface of an important member of the Cdc25 family, Cdc25B, and of sites of interaction between tested inhibitors and the protein, with emphasis on sites in the vicinity of the P-loop, a region close to the disordered C-terminus, where stability of the interaction with the small ligands is demonstrated

Traditional Chinese Medicine Treats Chronic Atrophic Gastritis via Multiple Pathways / 中国实验方剂学杂志

ObjectiveTo mine the compatibility rules of patented traditional Chinese medicine (TCM) compound prescriptions for treating chronic atrophic gastritis (CAG) by systems pharmacology and molecular docking methods, and predict the targets and molecular mechanisms of Chinese medicinals with different efficacy in the treatment of CAG. MethodThe TCM compound prescriptions for treating CAG were extracted from the patent system of the China National Intellectual Property Administration. The active components and targets of the prescriptions were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicine Integrative Database (TCMID), and UniProt. The candidate targets and pathways of CAG were obtained from GeneCards, DisGeNet, Online Mendelian Inheritance in Man (OMIM), MalaCards, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome. The gene ontology (GO) functional annotation and KEGG pathway enrichment were realized by R Studio 4.1.2. STRING11.0 was employed to build the protein-protein interaction (PPI) network, and AutoDock Vina 4.2.6 was used for the docking between key targets and components. ResultA total of 228 TCM compound prescriptions for treating CAG were extracted. The medicinals used in these prescriptions mainly had warm or cold nature, bitter or sweet taste, tropism to the spleen, stomach, and liver meridians, and the efficacy of tonifying Qi, regulating Qi movement, clearing heat, and activating and toniying blood. The prescriptions mainly treated CAG via p53, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), forkhead box protein O (FoxO), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1 (HIF-1) signaling pathways. Molecular docking results confirmed that the active components in the prescriptions had docking activities with key receptor proteins. ConclusionThis study preliminarily analyzed the compatibility rules of TCM compound prescriptions in the treatment of CAG. The medicinals with different efficacy treat CAG by regulating cell proliferation, apoptosis, and oxidative stress response, preventing carcinogen production, promoting gastric acid secretion, and improving local microcirculation in a multi-target, multi-pathway, multi-link manner. The findings facilitate the research on the TCM treatment of CAG.

Mechanism of Jindanjiangan Capsule in the treatment of hepatic fibrosis based on network pharmacology and molecular docking / 中国热带医学

@#Abstract: Objective To elucidate the potential mechanism of Jindanjiangan Capsule in the treatment of liver fibrosis by network pharmacology and molecular docking. Methods Active ingredients and targets of Jindanjiangan Capsules were searched by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and HERB databases, and the disease targets were screened by DisGeNET and Therapeutic Target Database (TTD) databases. The targets of the active ingredients of Jindanjiangan Capsule were matched with the disease targets, and the common targets were imported into the String database platform to construct a protein-protein interaction network (PPI) network. CytoNCA tool of Cytoscape 3.9.1 software was used for topological analysis to screen key targets. Traditional Chinese Medicine-Key Active IngredientsKey Target Network was constructed by Cytoscape 3.9.1 Software. KEGG enrichment analysis of key targets was performed through the DAVID platform. The molecular docking of active ingredients and targets was performed to verify the above results using LeDock software. Results By screening, 180 potential active ingredients and 1 340 targets of Jindanjiangan Capsule and 1 060 targets of liver fibrosis, and 273 common targets were obtained. 29 key targets related to liver fibrosis were screened out by PPI network interaction, and verified by KEGG analysis and molecular docking. Jindanjiangan capsule acts on key targets such as EGFR, MMP9, PTGS2, ESR1, PIK3CA, F2, PPARG, and PTPN11 through active components such as isovitexin, quercetin 7-O- β -D-glucoside, (3S, 6S) -3- (benzyl) -6- (4-hydroxybenzyl) piperazine-2, 5-quinone, 6-Osyringoyl-8-O-acetylshanzhiside methyl ester, tanshinone II, nortanshinone, capillaris chromone, and etanone. The specific mechanism may be related to HIF-1 signaling pathway, C-type lectin receptor signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, relaxin signaling pathway, FoxO signaling pathway and so on. Conclusion Jindanjiangan capsule can effectively treat hepatic fibrosis through multi-component, multi-target and multi-pathway.

Exploring the mechanism of action of curcumin in the treatment of silicosis based on network pharmacology and molecular docking / 中国职业医学

Objective To explore the mechanism of action of curcumin in the treatment of silicosis by network pharmacology combined with molecular docking technology. Methods The targets prediction network of curcumin in treating silicosis was established based on the collection of targets of curcumin and silicosis in multiple databases, cross-targets were submitted to the STRING database, and their connectivity was analyzed by Cytoscape software. Gene ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the top 20 genes. The molecular docking was performed on the key targets to study the mechanism of action of curcumin in treating silicosis. Results A total of 311 targets related to curcumin, 270 targets related to silicosis, and 74 cross-targets were obtained from the databases. GO function analysis revealed 2 665 related pathways, and KEGG pathway enrichment analysis revealed 188 related pathways. Molecular docking results showed that curcumin had good binding ability with the targets of mitogen-activated protein kinase 3 (MAPK3), interleukin (IL) 6, serine/threonine kinase 1 (AKT1), vascular endothelial growth factor A (VEGFA), signal transducer and activator of transcription 3, albumin, Jun proto-oncogene, tumor necrosis factor (TNF), IL1B, tumor protein p53, C-C motif chemokine ligand 2 and fibronectin 1. Conclusion The therapeutical effects of curcumin on silicosis were implemented through multi-targets and multi-pathways. Curcumin may play a role in the treatment of silicosis by binding to the core targets MAPK3, IL6, AKT1, VEGFA and TNF and regulating the MAPK, IL6, TNF, phosphatidylinositol 3-kinase/protein kinase B and VEGF signaling pathways.