A Comprehensive Review of Capsaicin and Its Role in Cancer Prevention and Treatment.

This study examines the fundamental chemical mechanisms responsible for capsaicin's advantageous impact on cancer, specifically investigating its influence on several biological processes such as inflammation in cancer metastasis, apoptosis, angiogenesis, and cellular proliferation. This entity's connections with other signaling pathways, including PI3K/AKT, NF-B, and TRPV channels, which have been linked to tumor growth, are thoroughly examined in this work. This study presents a thorough analysis of preclinical studies and clinical trials investigating the efficacy of capsaicin in treating many forms of cancer, such as breast, prostate, colorectal, pancreatic, and others. Through tests conducted in both live organisms and laboratory settings, it has been determined that capsaicin has the ability to inhibit tumor growth and induce apoptosis in cancer cells. (in vitro and in vivo). Researchers have also looked at the results of combining capsaicin with chemotherapy medications in traditional treatment. The efficacy and bioavailability of capsaicin as a viable medicinal drug are being studied, along with ways to improve its clinical value. The present investigation carefully assesses the challenges and potential options for maximizing the therapeutic benefits of capsaicin, including customized drug delivery and personalized therapeutic strategies. In finalization, this comprehensive investigation brings together the evidence currently obtainable on the anticancer properties of capsaicin, underscoring its potential as an autonomous treatment option in the struggle against cancer. Capsaicin is a compound of significant relevance for continuing research and clinical exploration in the field of cancer treatment due to its diverse mechanisms of action and ability for boosting prevailing therapy approaches.

Optimization of ultrasound-assisted extraction of bioactive chemicals from Hemidesmus indicus (L.) R.Br. using response surface methodology and adaptive neuro-fuzzy inference system.

This study was designed to optimize the ultrasound-assisted extraction (UAE) of bioactive chemicals from Hemidesmus indicus (L.) R.Br. through RSM (response surface methodology) and ANFIS (adaptive neuro-fuzzy inference system). The effect of four independent parameters, methanol concentration (X1: 55-65%), temperature (X2: 30-40 °C), time (X3: 15-20 min) and particle size (X4: 0.5-1.00 mm) at five levels (- 2 ,- 1, 0, + 1, + 2) with respect to dependent parameters, total polyphenols content (TP) (y1), total flavonoids content (TF) (y2), %DPPHsc (y3), %ABTSsc (y4) and %H2O2sc (y5) were selected. The optimal extraction condition was observed at X1 = 65%, X2 = 40 °C, X3 = 20 min and X4 = 0.5 mm; under this circumstance, y1 = 352.85 mg gallic acid equivalents (GA)/g, y2 = 300.204 mg rutin equivalents (RU)/g and their antioxidant potentials (y3 = 81.33%, y4 = 65.04%, and y5 = 71.01%) has been attained. ANFIS was used to compare and confirm the optimized extraction parameter values. Further, GC-MS and LC-MS were performed to investigate the bioactive chemicals present in the optimized extract. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01351-9.

Elucidating the role of phytocompounds from Brassica oleracea var. italic (Broccoli) on hyperthyroidism: an in-silico approach.

Thyroid hormone (TH) plays a crucial role in regulating the metabolism in every cell and all organs in of the human body. TH also control the rate of calorie burning, body weight, and function of the heartbeat. Therefore, the aim of the present study is to investigate the role of phytocompounds from Brassica oleracea var. italic (Broccoli) against irregularities of TH biosynthesis (hyperthyroidism) through in silico molecular modelling. Initially, the genetic network was built with graph theoretical network analysis to find the right target to control excessive TH production. Based on the network analysis, the three-dimensional crystal structure of the mammalian enzyme lactoperoxidase (PDB id: 5ff1) was retrieved from the protein data bank (PDB), and the active site was predicted using BIOVIA Discovery studio. Sixty-three phytocompounds were selected from the IMPPAT database and other literature. Selected sixty-six phytocompounds were docked against lactoperoxidase enzyme and compared with the standard drug methimazole. Based on the docking scores and binding energies, the top three compounds, namely brassicoside (- 10.00 kcal × mol-1), 24-methylene-25-methylcholesterol (- 9.50 kcal × mol-1), 5-dehydroavenasterol (- 9.40 kcal × mol-1) along with standard drug methimazole (- 4.10 kcal × mol-1) were selected for further ADMET and molecular dynamics simulation analysis. The top-scored compounds were for their properties such as ADMET, physicochemical and drug-likeness. The molecular dynamics simulation analyses proved the stability of lactoperoxidase-ligand complexes. The intermolecular interaction assessed by the dynamic conditions paved the way to discover the bioactive compounds brassicoside, 24-methylene-25-methylcholesterol, and 5-dehydroavenasterol prevent the excessive production of thyroid hormones. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00180-2.

An Integrated Computational and Experimental Approach to Formulate Tamanu Oil Bigels as Anti-Scarring Agent.

Tamanu oil has traditionally been used to treat various skin problems. The oil has wound-healing and skin-regenerating capabilities and encourages the growth of new skin cells, all of which are helpful for fading scars and hyperpigmentation, as well as promoting an all-around glow. The strong nutty odor and high viscosity are the major disadvantages associated with its application. The aim of this study was to create bigels using tamanu oil for its anti-scarring properties and predict the possible mechanism of action through the help of molecular docking studies. In silico studies were performed to analyze the binding affinity of the protein with the drug, and the anti-scarring activity was established using a full-thickness excision wound model. In silico studies revealed that the components inophyllum C, 4-norlanosta-17(20),24-diene-11,16-diol-21-oic acid, 3-oxo-16,21-lactone, calanolide A, and calophyllolide had docking scores of -11.3 kcal/mol, -11.1 kcal/mol, -9.8 kcal/mol, and -8.6 kcal/mol, respectively, with the cytokine TGF-ß1 receptor. Bigels were prepared with tamanu oil ranging from 5 to 20% along with micronized xanthan gum and evaluated for their pH, viscosity, and spreadability. An acute dermal irritation study in rabbits showed no irritation, erythema, eschar, or edema. In vivo excisional wound-healing studies performed on Wistar rats and subsequent histopathological studies showed that bigels had better healing properties when compared to the commercial formulation (MurivennaTM oil). This study substantiates the wound-healing and scar reduction potential of tamanu oil bigels.

Optimization of ultrasound-aided extraction of bioactive ingredients from Vitis vinifera seeds using RSM and ANFIS modeling with machine learning algorithm.

Plant materials are a rich source of polyphenolic compounds with interesting health-beneficial effects. The present study aimed to determine the optimized condition for maximum extraction of polyphenols from grape seeds through RSM (response surface methodology), ANFIS (adaptive neuro-fuzzy inference system), and machine learning (ML) algorithm models. Effect of five independent variables and their ranges, particle size (X1: 0.5-1 mm), methanol concentration (X2: 60-70% in distilled water), ultrasound exposure time (X3: 18-28 min), temperature (X4: 35-45 °C), and ultrasound intensity (X5: 65-75 W cm-2) at five levels (- 2, - 1, 0, + 1, and + 2) concerning dependent variables, total phenolic content (y1; TPC), total flavonoid content (y2; TFC), 2, 2-diphenyl-1-picrylhydrazyl free radicals scavenging (y3; %DPPH*sc), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) free radicals scavenging (y4; %ABTS*sc) and Ferric ion reducing antioxidant potential (y5; FRAP) were selected. The optimized condition was observed at X1 = 0.155 mm, X2 = 65% methanol in water, X3 = 23 min ultrasound exposure time, X4 = 40 °C, and X5 = 70 W cm-2 ultrasound intensity. Under this situation, the optimal yields of TPC, TFC, and antioxidant scavenging potential were achieved to be 670.32 mg GAE/g, 451.45 mg RE/g, 81.23% DPPH*sc, 77.39% ABTS*sc and 71.55 µg mol (Fe(II))/g FRAP. This optimal condition yielded equal experimental and expected values. A well-fitted quadratic model was recommended. Furthermore, the validated extraction parameters were optimized and compared using the ANFIS and random forest regressor-ML algorithm. Gas chromatography-mass spectroscopy (GC-MS) and liquid chromatography-mass spectroscopy (LC-MS) analyses were performed to find the existence of the bioactive compounds in the optimized extract.

In silico evaluation of some commercially available terpenoids as spike glycoprotein of SARS-CoV-2 - inhibitors using molecular dynamic approach.

Coronavirus, an extremely contagious infections disease had a harmful effect on the world's population. It is a family of enveloped, single-stranded, positive-strand RNA viruses of Nidovirales order belongs to coroviridae family. At present, worldwide several lakhs of deaths and several billions of infections have been reported. Hence, the focus of the present study was to assess the SARS-CoV-2 enzyme inhibitory potential of certain commercially available terpenoids using Lamarckian genetic algorithm as a working principle and molecular dynamic studies was also performed. AutoDock 4.2 software was used to perform the computational docking calculations of terpenoids against SARS-CoV-2 enzyme. The terpenoids such as, Andrographolide, Betulonic acid, Erythrodiol, Friedelin, Mimuscopic acid, Moronic acid, and Retinol were selected based on the drug likeness properties. Remdesivir a well-known anti-viral drug was selected as the standard drug. Molecular dynamic simulation studies were carried using Desmond module of Schrodinger Suite. In the current study we observed that, Friedelin was exhibited excellent SARS-CoV-2 enzyme inhibitory potential than the standard drug and other selected terpenoids. Friedelin and the standard Remdesivir was undergone the molecular dynamic studies and Friedelin showed a good number of hydrogen bonds over the simulation time of 100 ns. Based on the in silico computational evaluation, it can be concluded that Friedelin could be worthwhile terpenoid against SARS-CoV-2 spike protein. A further study on Friedelin is required to develop a potential chemical entity against the management of COVID disease.Communicated by Ramaswamy H. Sarma.

Mimosa pudica Linn. extract improves aphrodisiac performance in diabetes-induced male Wister rats.

Male sexual dysfunction is considered one of the major consequences of diabetes mellitus. The medicinal plant, Mimosa pudica Linn. is believed to have numerous therapeutic effects, including anti-diabetic, anti-obesity, aphrodisiac, and a sexual behaviour-enhancing properties. In the present study, the significant effect of ethanolic extract of M. pudica L. to scavenge excessive free radicals and alleviate the deleterious effects of alloxan-induced diabetes on the male sexual system of rats was demonstrated. The rats treated with the M. pudica L. extract recovered their body weight, the weight of their reproductive organs, the characteristics of the sperm and the histocellular arrangement of the testes. In addition, significant levels of hormones (testosterone, follicle-stimulating hormone and luteinising hormone) increased in both serum and testicular homogenates of male diabetic rats treated with M. pudica L. extract. Further, antioxidant enzymes, SOD, CAT, GSH, and GPx levels are increased, and oxidative stress markers MDA and ROS are reduced in both serum and testicular homogenates of M. pudica L. extract treated male rats. Furthermore, an in silico molecular docking study was performed to predict high potential compounds of M. pudica L. extract against the PDE5 receptor. Two bioactive compounds, namely 3-Dibenzofuranamine (-11.1 kcal × mol-1), Stigmasta-7,16-dien-3-ol (-10.4 kcal × mol-1) showed the highest binding affinities with PDE5 enzyme, much higher than the reference drug sildenafil (-9.9 kcal × mol-1). According to these findings, bioactive compounds rich in ethanolic extract of M. pudica L. have significant aphrodisiac performance in diabetic rats.Communicated by Ramaswamy H. Sarma.

A Review of PARP-1 Inhibitors: Assessing Emerging Prospects and Tailoring Therapeutic Strategies.

Eukaryotic organisms contain an enzyme family called poly (ADP-ribose) polymerases (PARPs), which is responsible for the poly (ADP-ribosylation) of DNA-binding proteins. PARPs are members of the cell signaling enzyme class. PARP-1, the most common isoform of the PARP family, is responsible for more than 90% of the tasks carried out by the PARP family as a whole. A superfamily consisting of 18 PARPs has been found. In order to synthesize polymers of ADP-ribose (PAR) and nicotinamide, the DNA damage nick monitor PARP-1 requires NAD+ as a substrate. The capability of PARP-1 activation to boost the transcription of proinflammatory genes, its ability to deplete cellular energy pools, which leads to cell malfunction and necrosis, and its involvement as a component in the process of DNA repair are the three consequences of PARP-1 activation that are of particular significance in the process of developing new drugs. As a result, the pharmacological reduction of PARP-1 may result in an increase in the cytotoxicity toward cancer cells.

Pharmacoinformatics-based identification of phytochemicals from Solanum torvum Swartz. fruits as potential inhibitors for MAPK14 protein.

Plants and phytocompounds gained more attention because of their unrivalled variety of chemical diversity. In this view, the present study was executed to predict the anticancer potential of Solanum torvum Swartz. fruits derived phytocompounds against one of the breast cancer target proteins (MAPK14, PDB ID: 5ETA, resolution: 2.80 Å) through pharmacoinformatics-based screening and molecular dynamics simulation tools. Initially, a graph theoretical network approach was used to visualize the genes, enzymes, and proteins involved in the signalling pathway of breast cancer and identify the significant target protein (MAPK14). A total of thirty-three active compounds were selected from S. torvum sw. through the IMPPAT database, and their structures were drawn by Chemsketch software. The drug-like behaviours of the compounds were assessed through pharmacokinetics and physicochemical characterization studies. Five compounds, namely chlorogenin (-10.90 kcal × mol-1), corosolic acid (-10.80 kcal × mol-1), solaspigenin (-10.80 kcal × mol-1), paniculogenin (-10.70 kcal × mol-1), spirostane-3,6-dione (-10.70 kcal × mol-1) exhibited top binding score against MAPK14, these are higher than that of the standard drug (Doxorubicin) (-8.60 kcal × mol-1). Additionally, the five top-binding compounds revealed better drug-likeness traits and the lowest toxicity profiles. MD simulation studies confirmed the stability of the top five scored compounds with the MAPK14 binding pockets. According to these findings, the selected five compounds might be used as significant MAPK14 inhibitors and can be used as new medicines for the treatment of breast cancer.Communicated by Ramaswamy H. Sarma.

An In Silico Molecular Modelling-Based Prediction of Potential Keap1 Inhibitors from Hemidesmus indicus (L.) R.Br. against Oxidative-Stress-Induced Diseases.

The present study investigated the antioxidant potential of aqueous methanolic extracts of Hemidesmus indicus (L.) R.Br., followed by a pharmacoinformatics-based screening of novel Keap1 protein inhibitors. Initially, the antioxidant potential of this plant extract was assessed via antioxidant assays (DPPH, ABTS radical scavenging, and FRAP). Furthermore, 69 phytocompounds in total were derived from this plant using the IMPPAT database, and their three-dimensional structures were obtained from the PubChem database. The chosen 69 phytocompounds were docked against the Kelch-Neh2 complex protein (PDB entry ID: 2flu, resolution 1.50 Å) along with the standard drug (CPUY192018). H. indicus (L.) R.Br. extract (100 µg × mL-1) showed 85 ± 2.917%, 78.783 ± 0.24% of DPPH, ABTS radicals scavenging activity, and 161 ± 4 µg × mol (Fe (II)) g-1 ferric ion reducing power. The three top-scored hits, namely Hemidescine (-11.30 Kcal × mol-1), Beta-Amyrin (-10.00 Kcal × mol-1), and Quercetin (-9.80 Kcal × mol-1), were selected based on their binding affinities. MD simulation studies showed that all the protein-ligand complexes (Keap1-HEM, Keap1-BET, and Keap1-QUE) were highly stable during the entire simulation period, compared with the standard CPUY192018-Keap1 complex. Based on these findings, the three top-scored phytocompounds may be used as significant and safe Keap1 inhibitors, and could potentially be used for the treatment of oxidative-stress-induced health complications.

Virtual Screening of a Marine Natural Product Database for In Silico Identification of a Potential Acetylcholinesterase Inhibitor.

Alzheimer's disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future.

A Review on Artificial Intelligence Approaches and Rational Approaches in Drug Discovery.

Artificial intelligence (AI) speeds up the drug development process and reduces its time, as well as the cost which is of enormous importance in outbreaks such as COVID-19. It uses a set of machine learning algorithms that collects the available data from resources, categorises, processes and develops novel learning methodologies. Virtual screening is a successful application of AI, which is used in screening huge drug-like databases and filtering to a small number of compounds. The brain's thinking of AI is its neural networking which uses techniques such as Convoluted Neural Network (CNN), Recursive Neural Network (RNN) or Generative Adversial Neural Network (GANN). The application ranges from small molecule drug discovery to the development of vaccines. In the present review article, we discussed various techniques of drug design, structure and ligand-based, pharmacokinetics and toxicity prediction using AI. The rapid phase of discovery is the need of the hour and AI is a targeted approach to achieve this.

Glucose-conjugated glutenin nanoparticles for selective targeting and delivery of camptothecin into breast cancer cells.

Receptor-mediated drug delivery systems are a promising tool for targeting malignant cells to suppress/inhibit the malignancy without disturbing healthy cells. Protein-based nanocarrier systems possess numerous advantages for the delivery of variety of chemotherapeutics, including therapeutic peptides and genes. In the present work, glucose-conjugated camptothecin-loaded glutenin nanoparticles (Glu-CPT-glutenin NPs) were fabricated to deliver camptothecin to MCF-7 cells via GLUT-1 transporter protein. Initially, Glu-conjugated glutenin polymer was successfully synthesized through reductive amination reaction, and this was confirmed by FTIR and 13C-NMR. Then, camptothecin (CPT) was loaded into Glu-conjugated glutenin polymer forming Glu-CPT-glutenin NPs. The nanoparticles were studied for their drug releasing capacity, morphological shape, size, physical nature, and zeta potential. The fabricated Glu-CPT-glutenin NPs were found to be spherical in shape and amorphous in nature with 200-nm size range and a zeta potential of - 30 mV. Furthermore, MTT assay using Glu-CPT-glutenin NPs confirmed concentration-dependent cytotoxicity against MCF-7 cells after 24-h treatment, and IC50 was found to be 18.23 µg mL-1. In vitro cellular uptake study demonstrated that the Glu-CPT-glutenin NPs had enhanced endocytosis and delivered CPT in MCF-7 cells. A typical apoptotic morphological change of condensed nuclei and distorted membrane bodies was found after treatment with IC50 concentration of NPs. The released CPT from NPs also targeted mitochondria of MCF-7 cells, significantly increasing the level of reactive oxygen species and causing the damage of mitochondrial membrane integrity. These outcomes confirmed that the wheat glutenin can positively serve as a significant delivery vehicle and enhance the anticancer potential of this drug.

Pharmacoinformatics-based screening of active compounds from Vitex negundo against lymphatic filariasis by targeting asparaginyl-tRNA synthetase.

CONTEXT: Lymphatic filariasis, generally called as elephantiasis, is a vector-borne infectious disease caused by the filarial nematodes, mainly Wuchereria bancrofti, Brugia malayi, and Brugia timori, which are transmitted through mosquitoes. The infection affects the normal flow of lymph leading to abnormal enlargement of body parts, severe pain, permanent disability, and social stigma. Due to the development of resistance as well as toxic effects, existing medicines for lymphatic filariasis are becoming ineffective in killing the adult worms. It is essential to search novel filaricidal drugs with new molecular targets. Asparaginyl-tRNA synthetase (PDB ID: 2XGT) belongs to the group of aminoacyl-tRNA synthetases that catalyze specific attachment of amino acids to their tRNA during protein biosynthesis. Plants and their extracts are well-known medicinal practice for the management of several parasitic infectious diseases including filarial infections. METHODS: In this study, asparaginyl-tRNA synthetase of Brugia malayi was used as a target to perform virtual screening of plant phytoconstituents of Vitex negundo from IMPPAT database, which exhibits anti-filarial and anti-helminthic properties. A total of sixty-eight compounds from Vitex negundo were docked against asparaginyl-tRNA synthetase using Autodock module of PyRx tool. Among the 68 compounds screened, 3 compounds, negundoside, myricetin, and nishindaside, exhibited a higher binding affinity compared to standard drugs. The pharmacokinetic and physicochemical prediction, stability of ligand-receptor complexes via molecular dynamics simulation, and density functionality theory were done further for the top-scored ligands with receptor.

Computational design of MmpL3 inhibitors for tuberculosis therapy.

Tuberculosis is a chronic communicable disease caused by Mycobacterium tuberculosis (Mtb) and spreads from lungs to lymphatic system. The cell wall of mycobacterium plays a prominent role in maintaining the virulence and pathogenicity and also acts as prime target for drug discovery. Hence, this study has put into emphasis with target MmpLs (Mycobacterial membrane proteins Large) which are significant for the growth and survival of Mycobacterium tuberculosis. MmpLs belongs to the resistance, nodulation and division (RND) protein superfamily. MmpL3 is the only MmpL deemed essential for the replication and viability of mycobacterial cells. For the study, we have selected SQ109 derivatives as Mmpl3 inhibitor, which holds non-covalent property. Structure-based pharmacophore model of MmpL3 target protein with SQ109 as co-crystallized ligand (PDB: 6AJG) was generated to screen the ligand database. Compounds with decent fitness score and pharmacophoric features were compared with standard drug and taken for molecular docking studies. Further prime molecular mechanics-Poisson-Boltzmann surface area (MM-GBSA) and induced fit calculations identified potential molecules for further drug-likeness screening. Overall computational calculations identified ZINC000000016638 and ZINC000000003594 as potential in silico MmpL3 inhibitors. Molecular dynamics simulations integrated with MM-PBSA free energy calculations identified that MmpL3-ZINC000000016638 complex was more stable. Study can be further extended for synthesis and biological evaluation, derivatization of active compound to identify potential and safe lead compounds for effective tuberculosis therapy.

Computational design of PD-L1 small molecule inhibitors for cancer therapy.

Drug repurposing opens new avenues in cancer therapy. Drug repurposing, or finding new uses for existing drugs, can substantially reduce drug discovery time and costs. Cheminformatics, genetics, and systems biology advances enable repositioning drugs. Clinical usage of PD-1/PD-L1 blocking has been approved because of its efficacy in improving prognosis in select groups. The PD-1/PD-L1 axis was considered to represent a mechanism for tumour evasion of host tumour antigen-specific T-cell immunity in early preclinical research. The expression of PD-L1 in cancer cells causes T lymphocytes to become exhausted by transmitting a co-inhibitory signal. A better understanding of how PD-L1 is regulated in cancer cells could lead to new therapeutic options. In this view, the study was aimed to repurpose the existing FDA-approved drugs as a potential PD-L1 inhibitor through e-Pharmacophore modelling, molecular docking and dynamic simulation. e-Pharmacophore screening retrieved 324 FDA-approved medications with the fitness score ≥ 1. The top 10-docked FDA candidates were compared with IN-35 (Clinical trial candidate) for its interaction pattern with critical amino acid residues. Mirabegron and Indacaterol exhibited a greater affinity for PD-L1 with docking scores of - 9.213 kcal mol-1 and - 8.023 kcal mol-1, respectively. Mirabegron retain interactions at all three major hotspots in the PD-L1 dimer interface similar to IN-35. MM-GBSA analyses indicated that Mirabegron uses less energy to create a more stable complex and retains all of the inhibitor's positive interactions found in clinical trial ligand IN-35. Molecular dynamics simulation analysis of the Mirabegron complex showed a similar pattern of deviation in correlation with IN-35, and it retains the interaction with the active key amino acids throughout the simulation time. Our present study has shown Mirabegron as a powerful inhibitor of PD-L1 expression in cancer cells using a drug-repurposing screen.

Design, synthesis, graph theoretical analysis and molecular modelling studies of novel substituted quinoline analogues as promising anti-breast cancer agents.

The most promising class of heterocyclic compounds in medicinal chemistry are those with the quinolin-2-one nucleus. It is a versatile heterocyclic molecule that has been put together with numerous pharmaceutical substances and is crucial in the creation of anticancer medications. In this view, the present research work deals with design, synthesis, and characterization of various analogous of quinolin-2-one nucleus and evaluation of their anticancer activity against MCF-7 cells (adenoma breast cancer cell line). Fourteen new compounds have been synthesised using suitable synthetic route and are characterized by FTIR, 1H NMR, 13C NMR and Mass spectral data. Molecular docking studies of the title compounds were carried out using PyRx 0.8 tool in AutoDock Vina program. All the synthesised compounds were exhibited well conserved hydrogen bonding with one or more amino acid residues in the active pocket of EGFR tyrosine kinase (PDB ID: 1m17). The docking score of the derivatives ranged from - 6.7 to - 9.5 kcal mol-1, standard drug Imatinib with - 9.6 kcal mol-1 and standard active ligand 4-anilinoquinazoline with - 7.7 kcal mol-1. The designed compound IV-A1 showed least binding energy (- 9.5 kcal mol-1) against EGFR tyrosine kinase receptor. Further, top scored compound, IV-A1 found to be most significant against MCF-7 cells with IC50 value of 0.0870 µM mL-1, TGI of 0.0958 µM mL-1, GI50 of 0.00499 µM mL-1, LC50 of 1.670 µM mL-1.

Cytotoxic Potential of Bioactive Compounds from Aspergillus flavus, an Endophytic Fungus Isolated from Cynodon dactylon, against Breast Cancer: Experimental and Computational Approach.

Endophytic fungi are a diverse group of microorganisms that colonize the inter- or intracellular spaces of plants and exhibit mutual benefits. Their interactions with the host plant and other microbiomes are multidimensional and play a crucial role in the production of secondary metabolites. We screened bioactive compounds present in the extracts of Aspergillus flavus, an endophytic fungus isolated from the roots of the medicinal grass Cynodon dactylon, for its anticancer potential. An in vitro analysis of the Ethyl acetate extract from A. flavus showed significant cytostatic effects (IC50: 16.25 µg/mL) against breast cancer cells (MCF-7). A morphological analysis of the cells and a flow cytometry of the cells with annexin V/Propidium Iodide suggested that the extract induced apoptosis in the MCF-7 cells. The extract of A. flavus increased reactive oxygen species (ROS) generation and caused a loss of mitochondrial membrane potential in MCF-7 cells. To identify the metabolites that might be responsible for the anticancer effect, the extract was subjected to a gas chromatography-mass spectrometry (GC-MS) analysis. Interestingly, nine phytochemicals that induced cytotoxicity in the breast cancer cell line were found in the extract. The in silico molecular docking and molecular dynamics simulation studies revealed that two compounds, 2,4,7-trinitrofluorenone and 3α, 5 α-cyclo-ergosta-7,9(11), 22t-triene-6beta-ol exhibited significant binding affinities (-9.20, and -9.50 Kcal/mol, respectively) against Bcl-2, along with binding stability and intermolecular interactions of its ligand-Bcl-2 complexes. Overall, the study found that the endophytic A. flavus from C. dactylon contains plant-like bioactive compounds that have a promising effect in breast cancer.

Aphrodisiac Performance of Bioactive Compounds from Mimosa pudica Linn.: In Silico Molecular Docking and Dynamics Simulation Approach.

Plants and their derived molecules have been traditionally used to manage numerous pathological complications, including male erectile dysfunction (ED). Mimosa pudica Linn. commonly referred to as the touch-me-not plant, and its extract are important sources of new lead molecules in drug discovery research. The main goal of this study was to predict highly effective molecules from M. pudica Linn. for reaching and maintaining penile erection before and during sexual intercourse through in silico molecular docking and dynamics simulation tools. A total of 28 bioactive molecules were identified from this target plant through public repositories, and their chemical structures were drawn using Chemsketch software. Graph theoretical network principles were applied to identify the ideal target (phosphodiesterase type 5) and rebuild the network to visualize the responsible signaling genes, proteins, and enzymes. The 28 identified bioactive molecules were docked against the phosphodiesterase type 5 (PDE5) enzyme and compared with the standard PDE5 inhibitor (sildenafil). Pharmacokinetics (ADME), toxicity, and several physicochemical properties of bioactive molecules were assessed to confirm their drug-likeness property. Molecular dynamics (MD) simulation modeling was performed to investigate the stability of PDE5-ligand complexes. Four bioactive molecules (Bufadienolide (-12.30 kcal mol-1), Stigmasterol (-11.40 kcal mol-1), Isovitexin (-11.20 kcal mol-1), and Apigetrin (-11.20 kcal mol-1)) showed the top binding affinities with the PDE5 enzyme, much more powerful than the standard PDE5 inhibitor (-9.80 kcal mol-1). The four top binding bioactive molecules were further validated for a stable binding affinity with the PDE5 enzyme and conformation during the MD simulation period as compared to the apoprotein and standard PDE5 inhibitor complexes. Further, the four top binding bioactive molecules demonstrated significant drug-likeness characteristics with lower toxicity profiles. According to the findings, the four top binding molecules may be used as potent and safe PDE5 inhibitors and could potentially be used in the treatment of ED.

Delivery of Ursolic Acid by Polyhydroxybutyrate Nanoparticles for Cancer Therapy: in silico and in vitro Studies.

Ursolic acid (UA), a pentacyclic triterpenoid and a phytochemical, is a potent inhibitory agent against proliferation of various tumors. Polyhydroxybutyrate nanoparticles (PHB NPs) are preferred in therapeutics due to their drug-stabilizing property and enhanced biological activity. In this study, PHB NPs were utilized to deliver and enhance the bioavailability of UA against cancer cells (HeLa). Further, molecular docking and dynamic studies were conducted to calculate the binding affinity and stability of UA at the active site of target protein (epidermal growth factor receptor-EGFR). The PHB NPs revealed the average size as 150-200 nm in TEM, which were used in subsequent experiments. The cytoplasmic uptake of nanoparticles was confirmed by florescent microscopy. The encapsulation potential of PHB NPs with UA was assessed by UV-visible spectrophotometer as 54%. Besides, the drug release behavior, cytotoxicity and the regulation of apoptosis were investigated in vitro. The cytotoxicity results revealed that the maximum efficiency of drug delivery was at 96th hour.