Analgesic, muscle relaxant, and anti-inflammatory potential of of flavonoids isolated from Euphorbia pulcherrima: Insights from molecular docking ligand retrieval, protein retrieval, and visualization and analysis investigation

Euphorbia pulcherrima is an important medicinal plant that is used in a traditional system for its curative properties such as analgesic potency, antipyretic, anti-inflammatory, sedation potential, and antidepressant and cure of diseases such as skin diseases. This study deals with the isolation of two flavonoids namely spinacetin (1) and patuletin (2) from chloroform fraction of Euphorbia pulcherrima. The isolated compound spinacetin (1) and patuletin (2) were screened for in vivo anti-inflammatory, analgesic, sedative, and muscle relaxant effects. Compounds 1 and 2 were assessed against hot plate-induced noxious stimuli at various doses which showed excellent (p < 0.05) analgesic effect in a dose-dependent manner. The muscle relaxant activity was determined by traction and inclined screening model, both compounds showed significant muscle relaxant activity with time. The sedative potential of isolated compounds 1 and 2 was determined by the open field model, both compounds showed good sedation (p < 0.05) at 20 mg/kg. The anti-inflammatory potential of compound 1 was recorded by histamine-induced paw edema and carrageen paw edema model, and in both models, compounds 1 and 2 showed strong effect at 20 mg/kg. Binding orientations, binding energy values, and computed inhibition constants (Ki) values revealed that the studied compounds have a good to excellent inhibition potential against μ-opioid receptors and COX-2.

Alzheimer's disease (AD) is a “progressive, neurodegenerative disease that occurs when nerve cells in the brain die.” There are only 4 drugs approved by the United States Food and Drug Administration (FDA). Three (donepezil, rivastigmine, and galantamine) out of these four drugs are anticholinesterase inhibitors, while the fourth one memantine is an N-methyl-D-aspartate (NMDA) receptor inhibitor. Currently, two immunotherapy drugs that target amyloid protein (donanemab and lecanemab) are being considered for the treatment of Alzheimer's disease at an early stage. All these drug molecules are still not the complete answer to the treatment of Alzheimer's disease. A recent report from the Office of National Statistics showed that AD is the leading cause of death in 2022. Therefore, there is an urgency to develop more drugs that can treat AD. Based on this urgency, we aim to investigate how bioactive and already approved drugs could be repurposed for inhibiting the anticholinesterase enzyme using computational studies. To achieve this, the data science tool—Python coding was compiled on Jupyter Notebook to mine bioactive compounds from the ChEMBL database. The most bioactive compounds obtained were further investigated using Molecular Operating Environment (MOE) software to carry out molecular docking and ligand analysis, and this was followed by molecular dynamics simulation production at 35 ns using GROMACS 2022.4 on Archer 2 machine. The molecular dynamic analysis was carried out using HeroMDanalysis software. Data mining of the ChEMBL database was carried out for lipase inhibitors, and this gave CHEMBL-ID 1240685, a peptide molecule, the most active compound at the time of data mining. Further literature studies gave Zoladex an FDA-approved drug for the treatment of breast cancer as another compound of interest. The in silico studies were carried out against the anticholinesterase enzyme using two FDA-approved drugs donepezil and galantamine as a template for comparing the in silico activities of the repurposed drugs. A very useful receptor for this study was PDB-1DX6, a cocrystallized galantamine inhibitor of acetylcholinesterase enzyme. The molecular docking analysis (using ligand interactions) and molecular dynamic analysis (root mean square deviation (RMSD) and root mean square fluctuation (RMSF)) showed that the two peptide molecules CHEMBL-1240685 and Zoladex gave the best binding energy and stability when compared to the FDA-approved drugs (donepezil and galantamine). Finally, further literature studies revealed that Zoladex affects memory reduction; therefore, it was dropped as a possible repurposed drug. Our research showed that CHEMBL-1240685 is a potential compound that could be investigated for the inhibition of anticholinesterase enzyme and might be another drug molecule that could be used to treat Alzheimer's disease.

1-Ethoxycarbonyl-beta-carboline inhibits the M2 polarization of tumor-associated macrophages: A study based on network pharmacology and molecular docking analyses

Anti-malarial proguanil (1) and phenoxypropoxy biguanide derivatives (2–9) are prodrugs. Their efficacy is directly proportional to the quantity of active triazine metabolites produced from these prodrugs. Detailed molecular docking analyses for all nine drug candidates in the active site of CYP3A4, CYP2D6, and CYP2C19 were carried out under the influence of induced-fit effect of ligand during molecular dynamic simulations. We have developed a strategy based on docking pose clusters to quantify the production of active metabolites for this class of molecules. For all drugs, site of metabolism based clusters of docking poses were prepared in both phases of the molecular docking analyses and correlated with the percentage of metabolites generated in the pooled human liver microsomes study. The total numbers of docking poses representing active metabolite formation were found to be well correlated with the experimental results in post-induced fit docking analyses. This strategy was first validated using proguanil, PS-15 and JPC-2056. Further, this methodology was employed to correlate the theoretically predicted metabolite formation of 4–9 to the experimentally estimated values which further led to clues on isoenzyme specificity in producing the metabolites. Binding requirements of these leads in the active sites of CYPs were also explored in this study.

Banxia Xiexin Decoction (BXD)is commonly used to treat a variety of gastrointestinal disorders, including Chronic Colitis (CC), due to its anti-inflammatory, antibacterial, and intestinal flora-regulating effects. However, CC is a chronic intestinal immunologic disease whose exact pathogenesis is unknown. Thus, more studies are needed to clarify the mechanism of action of BXD for CC treatment. The common components of BXD were validated by combining ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) analysis. Then, the mechanism of BXD for CC treatment was investigated using network pharmacology, including potential therapeutic CC phytochemicals, potential targets, and related signaling pathways. Molecular docking analysis was performed to investigate the protein-ligand interactions. Firstly, the chemical composition of BXD was determined by UPLC-QTOF- MS/MS technique and combined with TCMSP and HERB databases to determine the possible active ingredients in the formula, and the Uniprot database was used to find the targets corresponding to the ingredients; the disease targets related to CC were obtained by using GeneCards and Dis- GeNET databases. The intersection of component targets and disease targets was taken and imported into the STRING database for analysis, and then by Cytoscape 3.9.1 software, a protein-protein interaction network diagram (PPI) was constructed and the multi-level network of TCM-compoundtarget- disease was visualized, and DAVID database was used for GO and KEGG enrichment analysis of core genes. Finally, PyRx, AutoDockTools 1.5.6, PyMol 2.5.0, and Open Babel 2.4.1 were used for molecular docking, virtual computation, and visualization analyses of core components and key targets. UPLC-Q-TOF-MS/MS detected 482 components of BXD, Among the main components of BXD are flavonoids, triterpenoid saponins, alkaloids, glycosides, etc., and comprehensive analysis and screening yielded 165 active ingredients, including quercetin, kaempferol, baicalein, naringenin, etc. There were 283 targets related to BXD's treatment of CC, of which the core targets included AKT1, IL-6, TP53, ALB, etc. GO enrichment analysis yielded relevant entries including molecular function 60 entries, 257 entries of biological processes, and 31 entries of cellular composition, and KEGG enrichment analysis identified 150 entries involving IL-17, TNF, PI3K-Akt, and other pathways. The molecular docking results demonstrated that the core components exhibited better binding activities with the key targets. Quercetin, kaempferol, baicalein, and naringenin, the main active ingredients in BXD, may play roles in anti-inflammatory, antimicrobial, and regulating intestinal microbiota to achieve the therapeutic purpose of CC treatment by mediating the targets of AKT1, IL-6, TP53, and ALB, and regulating the signaling pathways of IL-17, TNF, and PI3K-Akt.

Aedes aegypti is the primary vector of dengue, a significant public health problem in many countries. Controlling of Ae. aegypti is the biggest challenge in the mosquito control programe, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission. To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1- phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis. All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects. Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC<50 and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM). The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programe.

Inflammatory response plays important roles in both tumorigenesis and carcinogenesis. In this study, secondary metabolite compounds from Lactococcus lactis subsp. lactis (Lac3) were analyzed by LC-MS and the potential inhibition activity against the COX-2 receptor was screened through molecular docking and molecular dynamics (MD) analysis. Anti-inflammatory agents, mofezolac and ibuprofen, were used as positive control ligands. The result indicates a potential COX-2 inhibitor of 5-[(4-Amino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]-2- methylbenzenesulfonate, which has a hydrogen bond on the active site Tyr385 of COX-2 with affinity energy of –9.0 kcal/mol. Moreover, another candidate of COX-2 inhibitor, designated as 3-Indolepropionic acid binds hydrogen on the important residue Ser530 of COX-2, with an affinity energy of –6.9 kcal/mol. To confirm the binding specificity, molecular docking analysis was also performed against COX-1. The binding stability and flexibility were confirmed using MD simulations. In addition, the toxicity and solubility of the potential ligands were predicted according to Lipinski’s rules and BOILED-Egg modeling. The 5-[(4-Amino-6-morpholin-4-yl- 1,3,5-triazin-2-yl)amino]-2-methylbenzenesulfonate shows the propensity for passive absorption through the gastrointestinal tract, whereas 3-Indolepropionic acid shows a high probability of blood-brain barrier penetration. In conclusion, this study identified potential compounds through molecular docking analysis which can be developed as COX-2 inhibitors.

The COVID-19 pandemic began in 2019 as a result of the advent of a novel coronavirus, SARS-CoV-2. At present, there are a limited number of approved antiviral agents for the treatment of COVID-19. Remdesivir, Molnupiravir, and Paxlovid have been approved by the FDA to treat COVID-19 infections. Research has shown that the main protease enzyme (Mpro) of SARS-CoV-2 plays a crucial role in the enzymatic processing of viral polyproteins. This makes Mpro an interesting therapeutic target for combating infections caused by emerging coronaviruses. The pharmacological effects of pyrroles and their derivatives have a wide range of applications. In our study, we focused on synthesizing nine novel derivatives of 2-arylamino-dihydro-indeno[1,2-b] pyrrol-4(1H)-one, with a particular emphasis on their antiviral properties. Using in silico studies involving molecular docking and DFT analyses in the gas phase using the B3LYP/6-31++G(d,p) basis set, we studied these compounds with respect to their interactions with the Mpro of SARS-CoV-2. The results of the docking analysis revealed that the synthesized compounds exhibited favorable inhibitory effects. Notably, compound 5f demonstrated the highest effectiveness against the target protein. Furthermore, the pharmacokinetic and drug-like properties of the synthesized derivatives of 2-arylamino-dihydroindeno[1,2-b] pyrrol-4(1H)-one indicated their potential as promising candidates for further development as inhibitors targeting SARS-CoV-2. However, it is imperative to determine the in vitro efficacy of these compounds through comprehensive biochemical and structural analyses.

Objective: This paper explores approaches to assess and compare the predicted enzymatic hydrolysis structures of specific mycotoxins in the active sites of CPA and CbhA enzymes using molecular docking analysis and molecular visualization and graphics tools. Methods: The tools used in this work included: The ChemBio3D Ultra software package, extensible molecular visualization and modeling systems (EMVMS) PyMol and UCSF Chimera, and AutoDock Vina 1.1.2 molecular docking software. Results: Visual binding of mycotoxins in the active centers of enzymes was shown, indicating possible enzymatic hydrolysis of ochratoxin A (OTA) in the active center of carboxypeptidase A (CPA) enzyme, as well as T-2 toxin and deoxynivalenol (DON) in the active center of cellobiohydrolase (CbhA) at the optimal pH (7.5 and 6, respectively) of enzyme action. Based on the results obtained from molecular docking using Autodock Vina 1.1.2 and EMVMSs UCSF Chimera and PyMol, it should be noted that according to the obtained affinities (kcal/mol), T-2 toxin binds best to the active site of CbhA enzyme (affinity value -7.8 kcal/mol); the next mycotoxin that binds best to the active site of CPA enzyme is OTA (affinity value -7.1 kcal/mol), followed by mycotoxin DON - to the active site of CbhA (affinity value -6.5 kcal/mol) at the optimal pH values of both enzymes. Conclusion: The binding energies of specific enzyme substrates are slightly lower for most of the ligand poses compared to the values obtained for mycotoxins, providing their higher affinities.

Ginger is a herb that can be used as an alternative medicine because it has anti-bacterial, antioxidant, anti-inflammatory, analgesic and antifungal properties. This study aims to identify the potency of red ginger ethanol extract against Candida albicans protein by using in silico and in vitro approaches. Several ginger-derived compounds were obtained from PubChem, while the target protein 4J14 was obtained from the Protein Data Bank (PDB) database. Prediction of Activity Spectra for Substances (PASS) Online was used to predict each compound’s biological function. Before molecular docking analysis, the 3D ligand site web server determined the binding site coordinates. PyRx was then used to perform molecular docking analysis on ginger compounds and the target protein 4J14, with fluconazole and posaconazole serving as controls. Additional analysis was used to identify amino acid residues in the complexes. The Chimera software was employed to describe protein compound complexes. The inhibitory zones of red ginger and fluconazole on fungal growth were determined in vitro. The molecular docking results showed that gamma-sitosterol had a more negative binding affinity (−9.6 kcal/mol) than fluconazole (−8.7 kcal/mol). Moreover, it affected the biological response of the target protein 4J14 or cytochrome 450, which is an essential protein in the fungal infection process. In vitro tests proved that a red ginger extract concentration of 15 mg/mL had antifungal potential. In silico and in vitro studies revealed that red ginger extract has the potential to be an antifungal agent. HIGHLIGHTS Since there have been numerous studies on the content of red ginger compounds with essential oils that have been shown to have antifungal potential, the fractionation approach was used to extract active compounds in red ginger that are devoid of essential oils in order to determine the antifungal potential The biological response of cytochrome 450, also known as target protein 4J14, is impacted by gamma-sitosterol. This protein is crucial for the mechanisms involved in fungal infection An extract from red ginger exhibited the same antifungal potential as fluconazole, according to in vitro experiments GRAPHICAL ABSTRACT

ABSTRACT‘Obesogens’ are chemical agents that improperly regulate the genes involved in glucose metabolism and adipocyte differentiation and promote lipid accumulation and adipogenesis. The human glucocorticoid receptor (hGR) is a steroid hormone triggered transcriptional factor and regulates target genes important in basal glucose homeostasis. Molecular docking analysis was performed in order to assess in-silico structure based toxic effects of high molecular weight phthalates dicyclohexyl phthalate (DCHP) and its monophthalate metabolite mono-cyclohexyl phthalate (MCHP). Molecular docking results show that the binding affinities of DCHP and MCHP lie in the comparable range (−7.87 kcal/mol and −6.24 kcal/mol) with Dexamethasone (−10.2 kcal/mol), a potent agonist for hGR. These two PAEs occupy the active site of hGR and interact with the key residues. Molecular simulation results infer that hGR-PAEs complexes were stable. Density functional theory (DFT) analysis indicates that HOMO and LUMO energy gap of DCHP (3.88 eV) and MCHP (3.39 eV) are comparable to DEX (4.69 eV). Binding free energy calculations of the DCHP-hGR and MCHP-hGR complexes were estimated by using Molecular Mechanic/Poisson-Boltzmann Surface Area (MMPBSA) method. Molecular Docking and simulation results emphasise that DCHP and MCHP can efficiently bind to hGR, which further leads to glucocorticoid-mediated adipogenesis in a synergistic manner.

Azadirachta indica A. Juss. is a well-known medicinal plant that has been used traditionally to cure various ailments in every corner of the globe. There are many in vitro and in vivo experimental evidences in connection with the bioactivity of the extracts of this plant. Lung cancer is the deadliest form of cancer and contributes to the most cancer related deaths. The mode of action of anticancer components of this plant is still to be established explicitly. The objective of this study is to identify druggable targets of active constituents of A. indica A. Juss. for non-small cell lung cancer (NSCLC) using network pharmacology and validation of activity through molecular docking analysis. Targets of all the active phytochemicals from A. indica were predicted and genes related to NSCLC were retrieved. A protein-protein interaction (PPI) network of the overlapping genes were prepared. Various databases and servers were employed to analyse the disease pathway enrichment analysis of the clustered genes. Validation of the gene/protein activity was achieved by performing molecular docking, and ADMET profiling of selected phytocompounds was performed. Gene networking revealed three key target genes as EGFR, BRAF and PIK3CA against NSCLC by the active components of A. indica. Molecular docking and ADMET analysis further validated that desacetylnimbin, nimbandiol, nimbin, nimbinene, nimbolide, salannin and vepinin are the best suited anti- NSCLC among all the phytocompounds present in this plant. The present study has provided a better understanding of the pharmacological effects of active components from A. indica and its potential therapeutic effect on NSCLC.

The development of targeted therapies for cancer and metabolic diseases remains a critical research area. The discovery of strong inhibitors of Pyruvate Dehydrogenase Kinase 1 (PDHK1), an enzyme essential for metabolic reprogramming, has been the focus of research in recent years. Doxifluridine, a prodrug of 5-fluorouracil, has shown promise for various cancer treatments. Additionally, its metabolites are of interest because of their potential medicinal effects. This paper presents a comprehensive computational molecular docking and dynamics analysis aimed at investigating the binding capabilities of doxifluridine and its metabolites as PDHK1 inhibitors. Molecular docking analysis revealed that doxifluridine and its metabolites displayed favorable binding interactions within the ATP-binding pocket of PDHK1, with docking scores of -11.84, -6.39, and -11.35 kcal/mol for doxifluridine, 5-fluorouracil, and 5-fluororouridine, respectively. The binding energies of these ligands (-37.32, -20.90, and -28.19 kcal/mol, respectively) suggest their potential inhibitory activity against PDHK1. Furthermore, specific amino acid residues involved in ligand binding have been identified, elucidating the key interactions required for stabilization. Molecular dynamics simulations reveal that these interactions are retained throughout a simulation period of 100 ns and the binding energy is -57.83±3.40 kcal/mol. URN:NBN:sciencein.jmc.2024.693

Treatment of Helicobacter pylori (H. pylori) infections faces challenges such as drug adherence, drug resistance, and re-infection. Surface antigens like BabA and SabA cause the disease, while phytochemicals like glycyrrhizin and cinnamaldehyde in liquorice and cinnamon are highly absorbed by H. pylori. Other molecules like coumarin can disrupt H. pylori adherence. Optimizing pharmacokinetics of certain drugs remain a challenge. Plant-derived chemical compounds can overcome treatment restrictions using molecular docking research, drug compatibility, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) examinations. These tools help to determine the appropriate usage of phytochemicals in bacteria. Our work aims to explore the potential of phytochemicals (glycyrrhizin, cinnamaldehyde, coumarin) as a treatment for H. pylori disease using molecular docking (BabA, SabA, CagA, VacA and urease) and ADMET analysis by in silico approaches. Glycyrrhizin has the most favorable binding energies with both CagA (− 8.9 kcal/mol) and VacA (− 8.4 kcal/mol), indicating stable interactions. Cinnamaldehyde and coumarin show weaker binding energies, suggesting less stability. Amoxicillin and clarithromycin showed moderate binding energy. Glycyrrhizin, cinnamaldehyde, and coumarin showed non-toxicity in assays, while amoxicillin and clarithromycin displayed toxicity, underscoring the importance of thorough safety assessments in drug development by ADMET study. Compounds meeting Lipinski's Rule of Five criteria, including cinnamaldehyde and coumarin, demonstrate potential for good oral bioavailability. Despite these difficulties, substances like coumarin, glycyrrhizin, and cinnamondehyde can be useful in the treatment of H. pylori. In-depth safety evaluations and continuous research are essential for improving medication development and promoting more effective H. pylori treatment.Graphical

Cytochrome P4501B1 is a ubiquitous family protein that is majorly overexpressed in tumors and is responsible for biotransformation-based inactivation of anti-cancer drugs. This inactivation marks the cause of resistance to chemotherapeutics. In the present study, integrated in-silico approaches were utilized to identify selective CYP1B1 inhibitors. To achieve this objective, we initially developed different machine learning models corresponding to two isoforms of the CYP1 family i.e. CYP1A1 and CYP1B1. Subsequently, small molecule databases including ChemBridge, Maybridge, and natural compound library were screened from the selected models of CYP1B1 and CYP1A1. The obtained CYP1B1 inhibitors were further subjected to molecular docking and ADMET analysis. The selectivity of the obtained hits for CYP1B1 over the other isoforms was also judged with molecular docking analysis. Finally, two hits were found to be the most stable which retained key interactions within the active site of CYP1B1 after the molecular dynamics simulations. Novel compound with CYP-D9 and CYP-14 IDs were found to be the most selective CYP1B1 inhibitors which may address the issue of resistance. Moreover, these compounds can be considered as safe agents for further cell-based and animal model studies. Communicated by Ramaswamy H. Sarma