Network pharmacology integrated molecular docking of fucoidan against oral cancer and in vitro evaluation- A study using GEO datasets.

Oral cancer is a widespread health concern in rural India due to a lack of awareness, delayed diagnosis and limited access to affordable treatment options. The current chemotherapy has notable side effects, underscoring the need for new drug candidates with improved bioavailability and specificity. In this current research, fucoidan, a sulphated polysaccharide, was extracted from the brown algae Spatoglossum asperum, and shown to be cytotoxic in vitro against oral cancer cells (KB cell line) at an IC50 of 107.76 µg/ml, suggesting its potential as a drug candidate. This study further aimed to explore the potential therapeutic implications of fucoidan in managing oral cancer using network pharmacology. PharmMapper, Comparative Toxicogenomics Database and SuperPred were initially used to identify fucoidan protein targets. The identified targets were further screened against Gene Expression Omnibus (GSE23558, GSE25099 and GSE146483), OMIM, TCGA and GeneCards datasets to identify oral cancer-specific protein targets. The interactions between the selected proteins were visualised using STRING and Cytoscape. Subsequently, Database for Annotation, Visualization and Integrated Discovery was used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of candidate targets. The cancer-related network was assessed using CancerGeneNet, while life expectancy based on the expression of the top 10 CytoHubba ranked hub genes was evaluated using Kaplan-Meier plots. Finally, EGFR, AKT1, HSP90AA1 and SRC were selected for docking and molecular dynamics simulation with fucoidan, using Maestro and GROMACS, respectively.Communicated by Ramaswamy H. Sarma.

2-[(E)-(2-carboxybenzylidene) amino] ethan ammonium-like amino acid zwitterions: crystal structure, functional studies and its molecular dynamic simulation study with drug target receptors.

The novel synthetic amino acid-like zwitterion containing imine bond ionic compound 2-[(E)-(2-carboxy benzylidene) amino] ethan ammonium salt, C10H12N2O2, was synthesized. Computational functional characterization is now being used to predict novel compounds. Here, we report on a titled combination that has been crystallizing in orthorhombic space group Pcc2 with Z = 4. The zwitterions form centrosymmetric dimers to polymeric supramolecular network via intermolecular N-H… O hydrogen bonds between the carboxylate groups and ammonium ion. The components are linked by ionic (N+-H-O-) and hydrogen bonds (N+-H-O), forming a complex three-dimensional supramolecular network. Further, molecular computational docking characterization study was performed with compound against multi-disease drug target biomolecule of anticancer target molecule of HDAC8 (PDB ID 1T69) receptor and antiviral molecular target protease (PDB ID 6LU7) to evaluate the interaction stability, conformational changes and to get insights into the natural dynamics on different timescales in solution. HighlightsThe novel zwitter ionic amino acid compound 2-[(E)-(2-carboxybenzylidene) amino] ethan ammonium salt, C10H12N2O2.The crystal structure determined for this compound illustrates the presence of intermolecular ionic N+-H-O- and N+-H-O hydrogen bonds between the carboxylate groups and ammonium ion, which influence the formation of a complex three-dimensional supramolecular polymeric network.Molecular docking studies helps to understand the conformational stability and interaction stabilityThe novel molecule can be considered for anticancer treatment.

Nickel sulfide and dysprosium-doped nickel sulfide nanoparticles: Dysprosium-induced variation in properties, in vitro chemo-photothermal behavior, and antibacterial activity.

Newer materials for utilization in multi-directional therapeutic actions are investigated, considering delicate design principles involving size and shape control, surface modification, and controllable drug loading and release. Multi-faceted properties are imparted to the engineered nanoparticles, like magnetism, near-infrared absorption, photothermal efficiency, and suitable size and shape. This report presents nickel sulfide and dysprosium-doped nickel sulfide nanoparticles with poly-ß-cyclodextrin polymer coating. The nanoparticles belong to the orthorhombic crystal systems, as indicated by X-ray diffraction studies. The size and shape of the nanoparticles are investigated using Transmission Electron Microscope (TEM) and a particle-size analyzer. The particles show soft ferromagnetic characteristics with definite and moderate saturation magnetization values. The nickel sulfide nanoparticles' in vitro anticancer and antibacterial activities are investigated in free and 5-fluorouracil/penicillin benzathine-loaded forms. The 5-fluorouracil-encapsulation efficiency of the nanoparticles is around 87%, whereas it is above 92% in the case of penicillin benzathine. Both drugs are released slowly in a controlled fashion. The dysprosium-doped nickel sulfide nanoparticles show better anticancer activity, and the efficacy is more significant than the free drug. The nanoparticles are irradiated with a low-power 808 nm laser. The dysprosium-doped nickel sulfide nanoparticles attain a higher temperature on irradiation, i.e., above 59 °C. The photothermal conversion efficiency of this material is determined, and the significance of dysprosium doping is discussed. Contrarily, the undoped nickel sulfide nanoparticles show more significant antibacterial activity. This study presents a novel designed nanoparticle system and the exciting variation of properties on dysprosium doping in nickel sulfide nanoparticles.

Synthesis and Biological Evaluation of 4-Aminoantipyrine Analogues.

OBJECTIVES: The aim of the present study is to carry out a simple synthesis of aminoantipyrine analogues and exploration of their antibacterial, cytotoxic, and anticonvulsant potential. METHODS: The compounds were characterized employing multi-spectroscopic methods. The in vitro pharmacological response of a series of bacteria was screened employing serial dilution method. The derivatives were screened against maximal electro-shock for their anticonvulsant activity. Molecular docking was carried out to optimize the interaction of the compounds with HPV16-E7 receptors. Further, the in vitro cytotoxicity was tested against human cervical cancer (SiHa) cell lines. RESULTS: The compounds show protection against maximal electroshock, esp. 3-nirto- and 4- methyl-3-nitrobenzamido derivatives. In addition, they reveal appreciable DNA cleavage activities and interactions with HPV16-E7 protein receptors, esp. 3,5-dinitro- and 4-methyl-3-nitrobenzamido derivatives. Furthermore, they show potent activity against cervical cancer cells (LD50 value up to 1200 in the case of 4-methyl-3-nitrobenzamido derivative and an inhibition of a maximum of ~97% of cells). CONCLUSION: The simply synthesized aminoantipyrine derivatives show a variety of biological activities like antibacterial and anticancer effects. In addition, this is the first study demonstrating that 4-aminoantipyrine derivatives show an anticonvulsant activity.

Computational Studies on T2Rs Agonist-Based Anti-COVID-19 Drug Design.

The expeditious and world pandemic viral disease of new coronavirus (SARS-CoV-2) has formed a prompt urgency to discover auspicious target-based ligand for the treatment of COVID-19. Symptoms of novel coronavirus disease (COVID-19) typically include dry cough, fever, and shortness of breath. Recent studies on many COVID-19 patients in Italy and the United Kingdom found increasing anosmia and ageusia among the COVID-19-infected patients. SARS-CoV-2 possibly infects neurons in the nasal passage and disrupts the senses of smell and taste, like other coronaviruses, such as SARS-CoV and MERS-CoV that could target the central nervous system. Developing a drug based on the T2Rs might be of better understanding and worth finding better molecules to act against COVID-19. In this research, we have taken a taste receptor agonist molecule to find a better core molecule that may act as the best resource to design a drug or corresponding derivatives. Based on the computational docking studies, the antibiotic tobramycin showed the best interaction against 6LU7 COVID-19 main protease. Aromatic carbonyl functional groups of the molecule established intermolecular hydrogen bonding interaction with GLN189 amino acid and it showed the two strongest carbonyl interactions with receptor protein resulting in a glide score of -11.159. To conclude, depending on the molecular recognition of the GPCR proteins, the agonist molecule can be recognized to represent the cell secondary mechanism; thus, it provides enough confidence to design a suitable molecule based on the tobramycin drug.

Myricetin: versatile plant based flavonoid for cancer treatment by inducing cell cycle arrest and ROS-reliant mitochondria-facilitated apoptosis in A549 lung cancer cells and in silico prediction.

Myricetin is categorized under the secondary metabolite flavonoid which includes a diverse range of consumable plant parts, and it has a potential against several classes of cancer including cancers and tumors. In the present study, the anticancer potential of the unique flavonoid-myricetin in A549 lung cancer cells was evaluated. Among different doses of myricetin, 73 µg/ml was more effective to prevent the cancer cell growth. It also promoted sub-G1 phase aggregation of cells and a equivalent decrease in the fraction of cells entering the S and subsequent phase which indicates apoptotic cell death. Myricetin generated enormous free radicals and, altered the potential of mitochondrial membrane in A549 cells as paralleled to untreated cells. In addition, myricetin treatment intensified the expression of P53 and relegated the expression of EGFR in A549 cells. These results suggested that myricetin exhibits cytotoxic potential by arresting the progression of cell cycle and ROS-dependent mitochondria-mediated mortality in cancer A549 lung cancer cells and it would be useful to develop as a drug candidate for lung cancer therapeutics. In silico experiments were carried out against human EGFR and P53 tumor suppressor protein to gain more insights into the binding mode of the myricetin may act as significant potential for anticancer therapy.

Computational studies on bacterial secondary metabolites against breast cancer.

Microbes exist in the human body provide more benefits by modulating metabolic processes, immunity, and signal transduction. However, microbial dysbiosis with harmful bacterial species can cause chronic inflammation and cancers. Hence human probiotics were recently paid more attention to immune responses, therapy, and diagnosis. Breast cancer is the second leading cancer worldwide and causes more death in women. The role of breast microbiome secondary metabolites in breast cancer is poorly studied. Research shows that breast has a specific microbiome inhabited with particular bacterial species. More significantly probiotics produced from breast microbiomes may act as a potential biomarker for breast cancer diagnosis. Hence this computational research aimed at the effect of chosen metabolites on breast cancer cell receptor G-protein-coupled bile acid receptor, Gpbar1 (TGR5). The current research suggested that cadaverine, succinate, p-cresol, and its derivatives could be used as a molecular marker in the diagnosis of breast cancer.

In silico structure prediction, molecular docking and dynamic simulation studies on G Protein-Coupled Receptor 116: a novel insight into breast cancer therapy.

G Protein-Coupled Receptor gains more importance in cancer research; because of their key role in several physiologic functions of cells. However, most of the GPCR's are orphan receptors, this hampers the finding of drugs against GPCR. G Protein-Coupled Receptor 116 is an adhesion orphan receptor that intensifies the invasion of cells in Triple-Negative Breast Cancer. In this study, existing FDA approved anticancer drugs were chosen as ligands and molecular docking was performed using in silico protein model of GPR116. Molecular interaction was analyzed carefully to identify the crucial amino acids present in binding pocket. Molecular dynamics simulations study executed to verify the structural and dynamic properties of Doxorubicin-GPR116 protein complex. The results have shown that Doxorubicin, Neratinib maleate, Epirubicin, and Lapatinib Ditosylate have good interaction with GPR116 binding site. Tyrosine 195 (Y195), Cysteine 196 (C196), Argenine 197 (R197), and Tryptophan 100 (W100) are commonly found in the majority of ligand-target interaction, hence based on the computational studies selective amino acids might be crucial for functional properties. Further to confirm crucial amino acids, computational mutation studies were executed. Molecular docking analysis with mutated GPR116 disclosed that significant variation in G score compared withligand-native protein interaction. Hence, the theoretical confirmatory structural properties changes support to prove selective crucial amino acids play the significant role in ligand binding. Molecular dynamic simulation results reveal that the interaction was stable throughout the MD simulation. To the best of our prognosis, GPR116 could be the best molecular target for breast cancer drug discovery.Communicated by Ramaswamy H. Sarma.

In silico molecular docking and physicochemical property studies on effective phytochemicals targeting GPR116 for breast cancer treatment.

G protein-coupled receptor 116 (GPR116), an orphan adhesion receptor, found an important role in cell adhesion and migration in eukaryotes. Abnormal expression of GPCR identified in various cancers turns focus of research community towards GPCR to identify the targeting drug against GPCR. Though GPR116 role was studied in progression of metastasis in triple-negative breast cancer (TNBC), unfortunately, still no drugs targeting GPR116 were identified. TNBC is a hormone-negative aggressive breast cancer found even in young women. Since TNBC has no target receptor for therapy, it would be desirable to target GPR116. Currently, chemotherapy is the only promising option for TNBC; however, these drugs cause chemoresistance. Hence this current study concentrated on finding drugable natural phytochemical ligands targeting GPR116 using in silico approach. Best docked ligand with target and active binding site amino acids were identified in molecular docking study. Pharmacokinetic properties (ADME) were assessed by Qikprop. Result showed that pharmacokinetics properties of natural phytochemicals were as good as existing chemotherapeutic cancer drugs. This study indicates that phytochemicals could be a promising target for GPR116. This in silico analysis facilitates further research to design the drug targeting GPR116 for treatment of TNBC.

Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics.

Many medications including antibiotics taste bitter. The potency of these antibiotics on the 25 bitter taste receptors (T2Rs) in humans remains poorly understood. Here we characterize by sensory and structure-function analyses how antibiotics frequently used to treat airway infections in cystic fibrosis activate multiple human T2Rs. The potency of the broad-spectrum antibiotics, tobramycin, levofloxacin, and azithromycin on the highly expressed T2Rs in airways, T2R4, T2R14, and T2R20 was pursued. The amino acids and structural features of T2R4, T2R14, and T2R20 important for antibiotic binding were characterized by mutational analysis in heterologous cell-based assays. Strikingly, extracellular loop 2 in T2Rs performs a key function in binding to antibiotics with contribution from residues in transmembrane helices. Our results suggest that different antibiotics activate multiple T2Rs with different potencies. An understanding of the nonantibiotic and physiologic effects mediated through T2Rs on the host cells is much needed.-Jaggupilli, A., Singh, N., De Jesus, V. C., Gounni, M. S., Dhanaraj, P., Chelikani, P. Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics.

A comparative meta-genomic analysis of HPV strains: A step towards the design, synthesis and characterization of noval quenazoline derivative for antiviral activity.

Epigenetic characterization studies have clearly shown that the association of genital Human Papilloma Virus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. Even though all the strains of Human Papilloma Virus can cause cancer, the high-risk strains can cause severe cancer in a human. The E6 and E7 protein are responsible for the carcinogenic property of HPV. Among these two proteins, the HPV E7 protein plays a major role in the viral life cycle by allowing the virus to replicate in differentiating epithelial cells. All the strains of HPV are variants (High risk and low risk). A computational analysis study is done to find which low-risk strain is showing most similarity with the high risk there by predicting that this low-risk strain can be converted to high-risk if a mutation occurs in future. Through mutation, a normal strain will get converted to low-risk and a low-risk to high-risk. So the mutations are important and it can affect the viruses to a greater extent because of their smaller size. In order to inhibit the expression of Type 11 low-risk strain a noval suppressor molecule is synthesized and characterized using UV, FTIR and NMR spectrometry. The suppressor molecule is a quinazoline derivative, as it can act as an anti-cancer agent to inhibit the expression of the E7 protein in Type 11 strain. The efficiency of binding of type 11 E7 protein with quinazoline derivative is calculated through docking studies using G-Score (Schrodinger). Thus proposing this noval suppressor molecule can be lead against cervical cancer caused by HPV Type 11 strain after further in-vitro and in vivo characterization.

Study of adenylyl cyclase-GαS interactions and identification of novel AC ligands.

Adenylyl cyclases (ACs) are membrane bound enzymes that catalyze the production of cAMP from ATP in response to the activation by G-protein Gαs. Different isoforms of ACs are ubiquitously expressed in different tissues involved in regulatory mechanisms in response to specific stimulants. There are 9 AC isoforms present in humans, with AC5 and AC6 proposed to play a vital role in cardiac functions. The activity of AC6 is sensitive to nitric oxide, such that nitrosylation of the protein might regulate its function. However, the information on structural determinants of nitrosylation in ACs and how they interact with Gαs is limited. Here we used homology modeling to build a molecular model of human AC6 bound to Gαs. Based on this 3D model, we predict the nitrosylation amenable cysteines, and identify potential novel ligands of AC6 using virtual ligand screening. Our model suggests Cys1004 in AC6 (subunit C2) and Cys174 in Gαs present at the AC-Gαs interface as the possible residues that might undergo reversible nitrosylation. Docking analysis predicted novel ligands of AC6 that include forskolin-based compounds and its derivatives. Further work involving site-directed mutagenesis of the predicted residues will allow manipulation of AC activity using novel ligands, and crucial insights on the role of nitrosylation of these proteins in pathophysiological conditions.

On the accessibility of surface-bound drugs on magnetic nanoparticles. Encapsulation of drugs loaded on modified dextran-coated superparamagnetic iron oxide by ß-cyclodextrin.

We report the loading of drugs on aminoethylaminodextran-coated iron oxide nanoparticles, their superparamagnetic behavior, loading of drugs on them, and the ß-cyclodextrin-complex formation of the drugs on the surface of the nanoparticles. The magnetic behavior is studied using vibrating sample magnetometry and X-ray photoelectron spectroscopy is used to analyze the elemental composition of drug-loaded nanoparticles. Scanning electron microscopy shows ordered structures of drug-loaded nanoparticles. UV-visible absorption and fluorescence spectroscopy are used to study the binding of the surface-loaded drugs to ß-cyclodextrin. All of the drugs form 1:1 host-guest complexes. The iodide ion quenching of fluorescence of free- and iron oxide-attached drugs are compared. The binding strengths of the iron oxide surface-loaded drugs-ß-cyclodextrin binding are smaller than those of the free drugs.

Chromenone-conjugated magnetic iron oxide nanoparticles. Toward conveyable DNA binders.

Magnetic nanoparticles can transport drug and possibly target cancer. DNA-binding of ligands loaded in dextran coated magnetic nanoparticles, could aid their better target-specific binding. In this work, we report the loading of chromenones onto aminoethylamino-modified dextran coated iron oxide nanoparticles, their loading efficiency, and openness for binding to DNA. The magnetic behavior, the size, and the morphology of the nanoparticles are analyzed. The crystallite size of the magnetic nanoparticles is around 40 nm. The chromenones are present on the surface of the dextran shell, as revealed by their cyclodextrin-binding characteristics, which is a new approach in comprehending the accessibility of the surface-bound molecules by macromolecules. The mode of binding of the chromenones to DNA is not altered on surface loading on dextran shell, although the binding strength is generally diminished, compared to the strength of binding of the free chromenones to DNA.

SIGLOCPRED: an algorithm to predict bacterial signal peptides and OMPS.

There is a growing interest in Biological investigation to determine the location of proteins, to identify new potentially accessible drug targets. Signal peptide directs the transport of the protein to its location. Bacterial OMPs are essential for their survival in the host organism. SIGLOCPRED a signal peptide predictor for the bacterial proteins as well as OMP prediction has been developed. The signal peptide prediction is done based on the influence of the flanking residues on the signal peptide cleavage. A dataset of proteins with confirmed outer membrane location has being created, and the probable OMP polypeptide sequence is predicted. Since the algorithm uses confirmed datasets the prediction is more reliable and efficient. SIGLOCPRED is as efficient as many of the existing signal peptide predictors and can also predict OMPs in addition.