Metabolomic profiling of three Araucaria species, and their possible potential role against COVID-19

Antifungal resistance represents a major challenge for treating invasive fungal infections due to the limited arsenal of systemic antifungal agents. Azole resistance among Candida and Aspergillus species and the spread of such species is alarming. Isoxazoles play a significant role in the field of medicinal chemistry. The great interest associated with this class of compounds is their versatility as synthetic intermediates. Isoxazole derivatives were found to possess anti-bacterial, anti-fungal, anti-inflammatory, pesticidal and herbicidal activities. This study focuses on screening some novel isoxazoles against essential enzymes of C. albicans using molecular docking and dynamic studies. Molecular docking studies were performed on twenty novel isoxazoles against N- methyl transferase and DNA gyrase of C. albicans using GLIDE. 2D and 3D dock poses were visualized. Molecular dynamic study was carried out by DESMOND. Docking study in the XP mode has given significant results with good GScores and Emodel for NMT. Compound 2D (2-hydroxy derivative) was ranked highest among the derivatives. The ligands bound tightly with the target protein, indicated by of hydrogen bond interactions and pi-pi stacking interactions at the active site. Molecular dynamic studies were carried out for two complexes. Complex was found to be stable during molecular dynamic simulation. Docking study suggests that compound 2D (2-hydroxy derivative) may be prospective inhibitors of N-methyl transferase as it are specific in binding to the active site of this enzyme. Hence it may be considered as lead molecule for the design of potential inhibitors of C. albicans.

In the present research work, we report the synthesis and characterization of novel pyrazole derivative obtained by the condensation reaction of 4-nitro benzaldehyde group with one equivalent of the 2-amino pyrazole yielding 4-nitro-N-1H-pyrazol-3-ylbenzamide with high yield. The two symmetry-independent molecules (molecule A and molecule B) differ about the central C-N bond, with the dihedral angles between the pyrazole ring system and the nitrobenzene ring being 13.90° and 18.64°, respectively. By optimizing the symmetry-independent dimer molecules, the rotational barrier between the conformers is found to be within the 2.5–5.5 kcal/mol range. QTAIM and RDG based NCI isosurface revealed the presence of strong N-H…N and C-H…O hydrogen bonds which stabilize the two independent centrosymmetric inversion-related dimers. Further, weak and short directional interactions such as C-H…N, H…H and C-H…π were also analyzed systematically using various topological parameters. The compound is found to adhere to the Lipinski’s rule of five and exhibit good pharmacokinetic properties. The results of molecular docking studies performed against SARS-CoV-2 virus main protease (PDB IDs: 6LU7, 6W9C and 6WQF) revealed that the compound showed better docking scores. Molecular docking studies verified the inhibition activity of the synthesized novel compound. Finally, the binding free energy and contributed energies were calculated using MM-GBSA method. The 6LU7-ligand complex showed highest binding free energy and among all other interactions, the contributions of the covalent binding and van der Waals energy are found to be significant. Communicated by Ramaswamy H. Sarma

BackgroundArdisia gigantifolia Stapf. (AGS), a Chinese folk medicine widely grows in the south of China and several studies reported that AGS could inhibit the proliferation of breast cancer, liver cancer, and bladder cancer cell lines. However, little is known about its anti-colorectal cancer (CRC) efficiency.MethodsIn the present study, a combination of MTT assay, network pharmacological analysis, bioinformatics, molecular docking, and molecular dynamics simulation study was used to investigate the active ingredients, and targets of AGS against CRC, as well as the potential mechanism.ResultsMTT assay showed that three kinds of fractions from AGS, including the n-butanol extract (NBAGS), ethyl acetate fraction (EAAGS), and petroleum ether fraction (PEAGS) significantly inhibited the proliferation of CRC cells, with the IC50 values of 197.24, 264.85, 15.45 µg/mL on HCT116 cells, and 523.6, 323.59, 150.31 µg/mL on SW620 cells, respectively. Eleven active ingredients, including, 11-O-galloylbergenin, 11-O-protocatechuoylbergenin, 11-O-syringylbergenin, ardisiacrispin B, bergenin, epicatechin-3-gallate, gallic acid, quercetin, stigmasterol, stigmasterol-3-o-β-D-glucopyranoside were identified. A total of 173 targets related to the bioactive components and 21,572 targets related to CRC were picked out through database searching. Based on the crossover targets of AGS and CRC, a protein-protein interaction network was built up by the String database, from which it was concluded that the core targets would be SRC, MAPK1, ESR1, HSP90AA1, MAPK8. Besides, GO analysis showed that the numbers of biological process, cellular component, and molecular function of AGS against CRC were 1079, 44, and 132, respectively, and KEGG pathway enrichment indicated that 96 signaling pathways in all would probably be involved in AGS against CRC, among which MAPK signaling pathway, lipid, and atherosclerosis, proteoglycans in cancer, prostate cancer, adherens junction would probably be the major pathways. The docking study verified that AGS had multiple ingredients and multiple targets against CRC. Molecular dynamics (MD) simulation analysis showed that the binding would be stable via forming hydrogen bonds.ConclusionOur study showed that AGS had good anti-CRC potency with the characteristics of multi-ingredients, -targets, and -signaling pathways.

Synthesis of novel antipyrine-azole-S-alkyl derivatives antimicrobial activity, molecular docking, and computational studies

Based on the lectotypes of Araucaria cunninghamii and A. heterophylla, the status of those species as cited in Chinese taxonomic literature, such as Flora of Guangzhou, Dendrology of China, Iconographia Cormo- phytorum Sinicorum, Flora Reipublicae Popularis Sinicae, Sylva Sinica, Flora of China and Higher Plants of China, was reviewed. Araucaria heterophylla has linear, acute juvenile leaves held at an angle of less than 45° to the branchlet and without an obvious adaxial keel and scale-like adult leaves on terminal branchlets; A. cunning- hamii has bilaterally compressed, subulate, shortly pungent juvenile leaves held at an angle of 45°-90° and with an obvious keel on both surfaces and tetragonous, subulate adult leaves on terminal branchlets. The names A. cunninghamii and A. heterophylla have been misapplied in Chinese taxonomic literature and should be A. hetero- phylla (Salisb.) Franco and A. cunninghamii Aiton ex A. Cunn. respectively. Key words Araucaria cunninghamii Aiton ex A. Cunn., Araucaria heterophylla (Salisb.) Franco, taxonomic revision.

Coronavirus disease 2019 (COVID-19) is a life intimidating viral infection caused by a positive sense RNA virus belonging to the Coronaviridae family, named severe acute respiratory distress syndrome coronavirus 2 (SARA-CoV-2). Since its outbreak in December 2019, the pandemic has spread to more than 200 countries, infected more than 26 million, and claimed the lives of more than 800,000 people. As a disease, COVID-19 can lead to severe and occasionally fatal respiratory problems in humans. Infection with this virus is associated with fever, cough, dyspnea, and muscle aches, and it may progress to pneumonia, multiple organ failure, and death. To date, there is no specific antiviral treatment against this virus. However, the main viral protease has been recently discovered and it is regarded as an appropriate target for antiviral agents in the search for the treatment of COVID-19, due to its pivotal role in polyproteins processing during viral replication. Consequently, this study intends to evaluate the effectiveness of FDA-approved anti-viral drugs against SARA-CoV-2 through a molecular docking study. AutoDock Vina in PyRx platform was used for docking analysis against the main viral protease (Mpro) (PDB ID 6LU7), and Computed Atlas of Surface Topography of proteins (CASTp 3.0) was applied for detecting and characterizing cavities, pockets, and channels of this protein structure. Results revealed that among the conventional antiviral drugs, the protease inhibitors, lopinavir, amprenavir, indinavir, maraviroc, saquinavir, and daclatasvir showed high binding affinity and interacted with amino acid residues of the binding site. In conclusion, protease inhibitors may be effective potential antiviral agents against Mpro to combat SARS-CoV-2.

The present work deals with the sequence of Novel Pyrazole fused Indole derivatives(4a-4l) were synthesized by simple conventional method andscreened for anthelmintic, antibacterial and anticancer activities. The molecular docking studies were also performed. All of the newly synthesizedcompounds were structurally characterized on the basis of IR, 1HNMR and Mass spectral analysis. Further, all of the newly prepared pyrazole fusedindole derivatives were screened for anthelmintic activity by using Albendazole as standard drug. The antibacterial activity was carried out by agardiffusion (Cup plate) method by using Streptomycin as standard and anticancer activity against MCF-7 cell lines by MTT assay method. The resultsshowed that some of the compounds 4b, 4c and 4f exhibited good anticancer activity. The compounds 4c, 4f, 4j showed good anthelmintic activity and4b,4h and 4i exhibited potential antibacterial activity by comparing with standard drug. Additionally, the molecular docking studies of novel pyrazolefused Indole derivatives was also carried out to explain putative bonding interaction between the active site of EGFR enzyme and synthesized NovelPyrazole fused Indole derivatives by Schrodinger suite.

The present study investigated the chemical composition, antioxidant potential, and molecular docking properties of Commiphora kerstingii essential oil (CKEO). Gas chromatography–mass spectrometry (GC–MS) analysis identified 25 compounds, with α-phellandrene (55.06 %), α-pinene (33.62 %), γ-muurolene (42 %), santolina triene (23 %), and ylangene (4.06 %) as the predominant constituents. Antioxidant assays revealed that CKEO exhibited concentration-dependent inhibition of free radicals. In the DPPH assay, the oil demonstrated 42.11–59.90 % inhibition across 2.5–10 µL/mL with an IC50 value of 1.667 ± 2 µL/mL, while vitamin C achieved higher inhibition (52.56–90.40 %) at the same concentrations. Similarly, in the H2O2 scavenging assay, CKEO showed inhibition values ranging from 44.46–72.08 % with an IC50 of 2.849 ± 2 µL/mL, compared to vitamin C (79.13–90.12 %). The result of this study revealed that Vitamin C which served as the standard reference drug demonstrated high antioxidant properties over the essential oil in both bioassays. Molecular docking studies further revealed γ-muurolene as the most active ligand among the tested compounds, with the best docking affinity against 8WEJ (–93.6306 kcal/mol), 8U85 (–64.1925 kcal/mol), and 8GZ3 (–67.8085 kcal/mol) protein receptors interactions. Although quercetin, used as a reference compound, exhibited superior docking scores. The results of the docking studies highlight the pharmacological potential of CKEO constituents, particularly γ-muurolene, as promising leads for antioxidant and therapeutic applications. The findings suggest that the bioactive compounds of C. kerstingii essential oil could serve as valuable natural agents for drug discovery.

From the fruits and seeds of the species of Pterodon, it is possible to obtain two main products: essential oil and oleoresin. In oleoresin, numerous vouacapan compounds have been demonstrated to have biological potential, including insecticidal activity. In silico studies were performed to identify potential candidates for natural insecticides among the vouacapans present in the genus Pterodon. Molecular docking and molecular dynamics studies were performed to analyze the interaction of vouacapan compounds with acetylcholinesterase of Drosophila melanogaster. Pharmacokinetic parameters regarding physicochemical properties, plasma protein binding, and activity in the central nervous system were evaluated. The toxicological properties of the selected molecules were predicted using malathion as the reference compound. 6α,7β-dimethoxivouacapan-17-ene (15) showed a high number of interactions and scores in molecular docking studies. These results suggested that this compound exhibits an inhibitory activity of the enzyme acetylcholinesterase. This compound showed the best results regarding physicochemical properties, besides presenting low cutaneous permeability values, suggesting null absorption. Molecular dynamics studies demonstrated few conformational changes in the structure of the complex formed by compound 4 and acetylcholinesterase enzyme throughout the simulation time. It was determined that compound 4 (vouacapan 6α,7β,17β,19-tetraol) could be an excellent candidate for usage as a natural insecticide.

COVID-19 (Coronavirus disease 2019) is a transmissible disease initiated and propagated through a new virus strain SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) since 31st December 2019 in Wuhan city of China and the infection has outspread globally influencing millions of people. Here, an attempt was made to recognize natural phytochemicals from medicinal plants, in order to reutilize them against COVID-19 by the virtue of molecular docking and molecular dynamics (MD) simulation study. Molecular docking study showed six probable inhibitors against SARS-CoV-2 Mpro (Main protease), two from Withania somnifera (Ashwagandha) (Withanoside V [10.32 kcal/mol] and Somniferine [9.62 kcal/mol]), one from Tinospora cordifolia (Giloy) (Tinocordiside [8.10 kcal/mol]) and three from Ocimum sanctum (Tulsi) (Vicenin [8.97 kcal/mol], Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte [8.55 kcal/mol] and Ursolic acid [8.52 kcal/mol]). ADMET profile prediction showed that the best docked phytochemicals from present work were safe and possesses drug-like properties. Further MD simulation study was performed to assess the constancy of docked complexes and found stable. Hence from present study it could be suggested that active phytochemicals from medicinal plants could potentially inhibit Mpro of SARS-CoV-2 and further equip the management strategy against COVID-19-a global contagion. Highlights Holistic approach of Ayurvedic medicinal plants to avenge against COVID-19 pandemic. Active phytoconstituents of Ayurvedic medicinal plants Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) predicted to significantly hinder main protease (Mpro or 3Clpro) of SARS-CoV-2. Through molecular docking and molecular dynamic simulation study, Withanoside V, Somniferine, Tinocordiside, Vicenin, Ursolic acid and Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte were anticipated to impede the activity of SARS-CoV-2 Mpro. Drug-likeness and ADMET profile prediction of best docked compounds from present study were predicted to be safe, drug-like compounds with no toxicity. Communicated by Ramaswamy H. Sarma

DNA groove binder and significant cytotoxic activity on human colon cancer cells: Potential of a dimeric zinc (II) phthalocyanine derivative

Conventional systems of medicine play a crucial role in maintaining healthcare. Herbal medicines are intact and less harmful to human beings than synthetic medicines. This study aimed to investigate the phytochemicals and in vivo hypolipidemic effect of chloroform extract of Lagenaria siceraria in Triton X-100 (100 mg/kg body weight) induced hyperlipidemic Wistar rats. The phytochemical characterization and estimation were performed on the base of the GC-MS approach. The Lagenaria siceraria extract (250 and 500 mg/kg bw) was administered orally to hyperlipidemic-induced rats for 7 days to examine its hypolipidemic activity. The experimental animals did not display any acute toxicity. Atorvastatin (10 mg/kg bw) was used as a standard drug. Administration of Lagenaria siceraria extract lowers the total cholesterol (TC), triglyceride (TG), and low-density lipoproteins-cholesterol (LDL-C) levels whereas elevating the high-density lipoproteins-cholesterol (HDL-C) level. Histological studies of the liver and heart also showed the hypolipidemic effect of the extract. On the 8th day, no inflammation of the liver, myocardial necrosis, fibrosis, or atypia was seen. Furthermore, binding affinity and plausible binding mode of stigmastan-3-ol with HMG-CoA reductase were predicted by molecular docking studies which showed the same interaction patterns as atorvastatin. Moreover, the docking results were refined by 100 ns MD simulations which revealed that stigmastan-3-ol extract formed a stable complex with protein and did not induce any conformational changes in protein structure.

This study explains the vibration and interaction of three pharmaceutically active hydrazine derivatives, (E)-3-((2-(2,5-difluorophenyl)hydrazono)methyl)-4H-chromen-4-one (DFH), (E)-3-((2-(4-(trifluoromethyl)phenyl)hydrazono)methyl)-4H-chromen-4-one (TMH), and (E)-3-((2-(3,5-bis(trifluoromethyl)phenyl)hydrazono)methyl)-4H-chromen-4-one (BPH) using theoretical approach. The trend in chemical reactivity and stability of the studied compounds was observed to show increasing stability and decreasing reactivity and this was obtained from orbital energies. The effect of bromine and chlorine atoms, instead of fluorine atoms, is also noted. Surface analysis on the covalent bond was attained by ELF and LOL analysis. Biological activities were predicted using molecular docking studies. Docking results were analyzed with standard drugs, 5-fluorouracil/piperine. Antitumor activity of hydrazine derivatives was found to be higher than reference ones. Molecular dynamics (MD) simulation was performed for 100ns to validate the stability behavior of hydrazine derivatives with the dual specificity threonine tyrosine kinase (TTK) protein. RMSD, RMSF, Rg, SASA, and intermolecular analysis of DFH, TMH, and BPH with threonine tyrosine kinase forms stable ligand-protein interactions. The molecular and predictive biological properties of three pharmaceutically active hydrazine derivatives which can be helpful to researchers in future experimental validation through in vitro and in vivo studies.

Density functional theory (DFT), molecular docking, and xanthine oxidase inhibitory studies of dinaphthodiospyrol S from Diospyros kaki L

BackgroundThe most well-known cause of cancer deaths identified in female is breast cancer. Several drugs approved by the food and drug administration (FDA) for the treatment of breast cancer may have adverse health effects. This research is aimed at developing a QSAR model and utilize it to predict the inhibitive activities of newly designed novel compounds, examine their ADMET and drug-likeness properties and carry out molecular docking studies between the designed compounds and the VEGFR-2 receptors in order to identify the essential amino acid residues involved in protein–ligand interactions and possible mechanism of action of the designed compounds.ResultsThe first model was selected as the best because of its fitness statistically with the following assessment parameters: R2train = 0.832, R2adj = 0.79, R2ext = 0.62, Q2 = 0.68, and LOF = 0.14509. Compound 11 was selected as a template to design new powerful compounds based on its low residual and high pIC50 values. Majority of the designed compounds has predicted pIC50 greater than that of the lead compound and the standard drug (Sunitinib) used as reference. Molecular docking studies results of the designed compounds revealed that they have higher docking scores than the template and the reference drug (Sunitinib) and are found to bind to the VEGFR-2 receptor in a similar manner to the reference drug. Pharmacokinetics and ADMET properties revealed that the designed compounds passed drug-likeness criteria because they did not violate more than 1 Lipinski’s rule of Five, They are uniformly distributed to the brain and are assumed to penetrate the central nervous system and finally they are all found to non-toxic and orally bioavailable.ConclusionThe developed model was therefore found to be efficient in predicting the pIC50 of Anti breast cancer compounds that are yet to be synthesized and it also help in reducing the cost and synthetic duration the compounds. The result of this research confirmed that the designed compounds may be developed as novel VEGFR-2 inhibitors.