Formulation Studies with Cyclodextrins for Novel Selenium NSAID Derivatives.

Commercial cyclodextrins (CDs) are commonly used to form inclusion complexes (ICs) with different molecules in order to enhance their water solubility, stability, and bioavailability. Nowadays, there is strong, convincing evidence of the anticancer effect of selenium (Se)-containing compounds. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their further evaluation and clinical use. In this work, we study the enhancement of solubility with CD complexes for a set of different nonsteroidal anti-inflammatory drug (NSAID) derivatives with Se as selenoester or diacyl diselenide chemical forms, with demonstrated antitumoral activity. The CD complexes were analyzed via nuclear magnetic resonance (NMR) spectroscopic techniques. In order to obtain additional data that could help explain the experimental results obtained, 3D models of the theoretical CD-compound complexes were constructed using molecular modeling techniques. Among all the compounds, I.3e and II.5 showed a remarkable increase in their water solubility, which could be ascribed to the formation of the most stable interactions with the CDs used, in agreement with the in silico studies performed. Thus, the preliminary results obtained in this work led us to confirm the selection of ß and γ-CD as the most suitable for overcoming the pharmaceutical drawbacks of these Se derivatives.

Large-scale computational screening of Indian medicinal plants reveals Cassia angustifolia to be a potentially anti-diabetic.

Researchers are investigating the medicinal properties of herbal plants throughout the world, which often leads to the discovery of novel plants and their chemicals for prophylactic needs of humans. Natural phytochemicals continue to be sought as alternative treatments for various diseases because of their non-toxic and therapeutic properties. In recent years, computational phytochemistry has enabled large-scale screening of phytochemicals, enabling researchers to pursue a wide range of therapeutic research alternatives to traditional ethnopharmacology. We propose to identify an anti-diabetic plant by computational screening on Indian herbal plants in conjunction with experimental characterization and biological validation. The methodology involves the creation of an in-house Indian herbal plant database. Molecular docking is used to screen against alpha amylase for anti-diabetic prophylaxis. Cassia angustifolia was chosen because its phytochemicals are able to bind to alpha amylase. Plants were experimentally extracted, botanically studied and their biological activity was evaluated. Further, the use of molecular dynamics was then applied to pinpoint the phytochemicals responsible for the affinity of alpha amylase. Results in the phytochemical analysis of the extracts revealed strong presence of alkaloids, flavonoids and cardiac glycosides. Moreover, alpha amylase biological activity with C. angustifolia extracts of chloroform, hexane and ethyl acetate demonstrated activity of 3.26, 8.01 and 30.33 µg/ml validating computational predictions. In conclusion, this study developed, validated computational predictions of identifying potential anti-diabetic plants 'Cassia angustifolia' from house herbal databases. Hope this study shall inspire explore plant therapeutic repurposing using computational methods of drug discovery.Communicated by Ramaswamy H. Sarma.

In-house database phytochemicals preparation using Indian medicinal plants for repurposing plant therapeutics screening.Virtual screening of in-house database against alpha amylase for anti-diabetic therapeutics.The highest affinity plants Cassia angustifolia were identified, collected, processed four solvent extracts, along with qualitative and quantitative estimations.All plant extracts are subjected to botanical and biological experimental perspective.Advanced molecular dynamics simulations are used to understand the non-bonding interactions of phytochemicals with alpha amylase.

Antifungal and Antiproliferative Activity of Pistagremic Acid and Flavonoids Extracted from the Galls of Pistacia chinensis subsp. integerrima.

Pistacia chinensis subsp. integerrima (J.L. Stewart) Rech. f. is a plant known for its therapeutic applications in traditional medicine, which are related to its antimicrobial, anticancer, antioxidant, anti-inflammatory, analgesic, antidiarrheal, and muscle relaxant properties. The galls of P. chinensis are rich in triterpenes and flavonoids, and we here report the extraction of pistagremic acid (1), apigenin (2) and sakuranetin (3) from this source. The isolated compounds were tested against Aspergillus flavus, Candida albicans, Candida glabrata, Fusarium solani, Microsporum canis and Trichoderma longibrachiatum. The results highlighted the antimicrobial activity of flavonoids 2 and 3, suggesting that this class of molecules may be responsible for the effect related to the traditional use. On the other hand, when the compounds and the extract were tested for their antiproliferative activity on a panel of 4 human cancer cell lines, the triterpene pistagremic acid (1) showed a higher potential, thus demonstrating a different bioactivity profile. Structure-based docking and molecular dynamics simulations were used to help the interpretation of experimental results. Taken together, the here reported findings pave the way for the rationalization of the use of P. chinensis extracts, highlighting the contributions of the different components of galls to the observed bioactivity.

Attenuation of quorum sensing regulated virulence functions and biofilm of pathogenic bacteria by medicinal plant Artemisia annua and its phytoconstituent 1, 8-cineole.

The emergence of multidrug resistance (MDR) in bacterial pathogens is a serious public health concern. A significant therapeutic target for MDR infections is the quorum sensing-regulated bacterial pathogenicity. Determining the anti-quorum sensing abilities of certain medicinal plants against bacterial pathogens as well as the in-silico interactions of particular bioactive phytocompounds with QS and biofilm-associated proteins were the objectives of the present study. In this study, 6 medicinal plants were selected based on their ethnopharmacological usage, screened for Anti-QS activity and Artemisia annua leaf extract (AALE) demonstrated pigment inhibitory activity against Chromobacterium violaceum CV12472. Further, the methanol active fraction significantly inhibited the virulence factors (pyocyanin, pyoverdine, rhamnolipid and swarming motility) of Pseudomonas aeruginosa PAO1 and Serratia marcescens MTCC 97 at respective sub-MICs. The inhibition of biofilm was determined using a microtiter plate test and scanning electron microscopy. Biofilm formation was impaired by 70%, 72% and 74% in P. aeruginosa, C. violaceum and S. marcescens, respectively at 0.5xMIC of the extract. The phytochemical content of the extract was studied using GC-MS and 1, 8-cineole was identified as major bioactive compound. Furthermore, 1, 8-cineole was docked with quorum sensing (QS) proteins (LasI, LasR, CviR, and rhlR) and biofilm proteins (PilY1 and PilT). In silico docking and dynamics simulations studies suggested interactions with QS-receptors CviR', LasI, LasR, and biofilm proteins PilY1, PilT for anti-QS activity. Further, 1, 8-cineole demonstrated 66% and 51% reduction in violacein production and biofilm formation, respectively to validate the findings of computational analysis. Findings of the present investigation suggests that 1, 8-cineole plays a crucial role in the QS and biofilm inhibitory activity demonstrated by Artemisia annua extract. RESEARCH HIGHLIGHTS: Artemisia annua leaf extract (AALE) methanol fraction demonstrated broad-spectrum QS and biofilm inhibition Scanning electron microscopy (SEM) confirmed biofilm inhibition Molecular docking and simulation studies suggested positive interactions of 1,8-cineol with QS-receptors and biofilm proteins.

SARS-CoV-2 Main Protease Inhibitors from Natural Product Repository as Therapeutic Candidates for the Treatment of Coronaviridae Infections.

BACKGROUND: The main protease (Mpro) is a crucial enzyme for the life cycle of SARS-CoV-2 and a validated target for the treatment of COVID-19 infection. Natural products have been a proper alternative for treating viral diseases by modulating different steps of the life cycle of many viruses. OBJECTIVE: This review article is designed to summarize the cumulative information of natural-derived Mpro inhibitors that are validated by experimental biological testing. METHODS: The natural-derived Mpro inhibitors of SARS-CoV-2 that have been discovered since the emergence of the COVID-19 pandemic are reviewed in this article. Only natural products with experimental validation are reported in this article. Collected compounds are classified according to their chemical identity into flavonoids, phenolic acids, quinones, alkaloids, chromones, stilbenes, tannins, lignans, terpenes, and other polyphenolic and miscellaneous natural-derived Mpro inhibitors. CONCLUSION: These compounds could serve as scaffolds for further lead-structure optimization for desirable potency, a larger margin of safety, and better oral activity.

Structural insights into modeling of hepatitis B virus reverse transcriptase and identification of its inhibitors from potential medicinal plants of Western Ghats: an in silico and in vitro study.

The present study was proposed to model full-length HBV-RT and investigate the intermolecular interactions of known inhibitor and libraries of phytocompounds to probe the potential natural leads by in silico and in vitro studies. Homology modeling of RT was performed by Phyre2 and Modeller and virtual screening of ligands implemented through POAP pipeline. Molecular dynamics (MD) simulation (100 ns) and MM-GBSA calculations were performed using Schrodinger Desmond and Prime, respectively. Phytocompounds probable host protein targets gene set pathway enrichment and network analysis were executed by KEGG database and Cytoscape software. Prioritized plant extracts/enriched fraction LC-MS analysis was performed and along with pure compound, RT inhibitory activity, time-dependent HBsAg and HBeAg secretion, and intracellular HBV DNA, and pgRNA by qRT-PCR was performed in HepG2.2.15 cell line. Among the screened chemical library of 268 phytocompounds from 18 medicinal plants, 15 molecules from Terminalia chebula (6), Bidens pilosa (5), and Centella asiatica (4)) were identified as potential inhibitors of YMDD and RT1 motif of HBV-RT. MD simulation demonstrated stable interactions of 15 phytocompounds with HBV-RT, of which 1,2,3,4,6-Pentagalloyl Glucose (PGG) was identified as lead molecule. Out of 15 compounds, 11 were predicted to modulate 39 proteins and 15 molecular pathways associated with HBV infection. TCN and TCW (500 µg/mL) showed potent RT inhibition, decreased intracellular HBV DNA, and pgRNA, and time-dependent inhibition of HBsAg and HBeAg levels compared to PGG and Tenofovir Disoproxil Fumarate. We propose that the identified lead molecules from T. chebula as promising and cost-effective moieties for the management of HBV infection.Communicated by Ramaswamy H. Sarma.

Exploring therapeutic targets and drug candidates for obesity: a combined network pharmacology, bioinformatics approach.

The remarkably high prevalence of obesity in Saudi Arabia reflects a global epidemic demanding urgent attention due to its associated health risks. The integration of traditional medicine, a vital cultural aspect, involves the use of medicinal plants to address various diseases, including obesity. This research merges network pharmacology (NP) and bioinformatics to innovate obesity treatment by identifying effective phytochemicals from native plants in the Taif valley. Focusing on six indigenous plants-Senna alexandrina, Capsicum annuum, Zingiber officinale, Curcuma longa, Trigonella foenum-graecum, and Foeniculum vulgare-we conducted preliminary screenings for potential bioactive compounds. We systematically compiled compound data from public databases and reviewed literature, revealing active compounds like apigenin, kaempferol, moupinamide, cyclocurcumin, chrysoeriol, isorhamnetin, rheinanthrone, cyclocurcumin, and riboflavin.Constructing a compound-target genes-obesity network unveiled their significant impact on metabolic regulation and fat accumulation, interacting notably with key proteins AKT1 and PTGS2. Molecular docking and 100 ns Molecular Dynamic (MD) simulations demonstrated robust binding affinity and stability at the docking site. Employing adipocytes as a cellular model, we gauged their viability and response to obesity-related stressors post-treatment with these native plant compounds.In conclusion, Saudi Arabia's indigenous plants hold promise as natural solutions for obesity treatment. This research opens new avenues in the battle against this pervasive health crisis by incorporating the potential of native botanicals.Communicated by Ramaswamy H. Sarma.

The Potential Roles of Ficus carica Extract in the Management of COVID-19 Viral Infections: A Computer-Aided Drug Design Study.

INTRODUCTION: The conventional processes of drug discovery are too expensive, time-consuming and the success rate is limited. Searching for alternatives that have evident safety and potential efficacy could save money, time and improve the current therapeutic regimen outcomes. METHOD: Clinical phytotherapy implies the use of extracts of natural origin for prophylaxis, treatment, or management of human disorders. In this work, the potential role of common Fig (Ficus carica) in the management of COVID-19 infections has been explored. The antiviral effects of Cyanidin-3-rhamnoglucoside which is abundant in common Figs have been illustrated on COVID-19 targets. The immunomodulatory effect and the ability to ameliorate the cytokine storm associated with coronavirus infections have also been highlighted. This work involves various computational studies to investigate the potential roles of common figs in the management of COVID-19 viral infections. RESULTS: Two molecular docking studies of all active ingredients in common Figs were conducted starting with MOE to provide initial insights, followed by Autodock Vina for further confirmation of the results of the top five compounds with the best docking score. CONCLUSION: Finally, Molecular dynamic simulation alongside MMPBSA calculations were conducted using GROMACS to endorse and validate the entire work.

The structural characterization and bioactivity assessment of nonspecific lipid transfer protein 1 (nsLTP1) from caraway (Carum carvi) seeds.

BACKGROUND: Carum carvi (caraway) of the Apiaceae family has been used in many cultures as a cooking spice and part of the folk medicine. Previous reports primarily focus on the medicinal properties of caraway seed essential oil and the whole seeds extract. However, no effort has been made to study caraway proteins and their potential pharmacological properties, including nonspecific lipid transfer protein (nsLTP), necessitating further research. The current study aimed to characterize nonspecific lipid transfer protein 1 (nsLTP1) from caraway seed, determine its three-dimensional structure, and analyze protein-ligand complex interactions through docking studies. We also evaluated nsLTP1 in vitro cytotoxic effect and antioxidant capacity. Additionally, nsLTP1 thermal- and pH- stability were investigated. METHODS: Caraway nsLTP1 was purified using two-dimensional chromatography. The complete amino acid sequence of nsLTP1 was achieved by intact protein sequence for the first 20 residues and the overlapping digested peptides. The three-dimensional structure was predicted using MODELLER. Autodock Vina software was employed for docking fatty acids against caraway nsLTP1. Assessment of nsLTP1 cytotoxic activity was achieved by MTS assay, and the Trolox equivalent antioxidant capacity (TAC) was determined. Thermal and pH stability of the nsLTP1 was examined by circular dichroism (CD) spectroscopy. RESULTS: Caraway nsLTP1 is composed of 91 residues and weighs 9652 Da. The three-dimensional structure of caraway nsLTP1 sequence was constructed based on searching known structures in the PDB. We chose nsLTP of Solanum melongena (PDB ID: 5TVI) as the modeling template with the highest identity among all other homologous proteins. Docking linolenic acid with caraway protein showed a maximum binding score of -3.6 kcal/mol. A preliminary screening of caraway nsLTP1 suppressed the proliferation of human breast cancer cell lines MDA-MB-231 and MCF-7 in a dose­dependent manner with an IC50 value of 52.93 and 44.76 µM, respectively. Also, nsLTP1 (41.4 µM) showed TAC up to 750.4 µM Trolox equivalent. Assessment of nsLTP1 demonstrated high thermal/pH stability. CONCLUSION: To the best of our knowledge, this is the first study carried out on nsLTP1 from caraway seeds. We hereby report the sequence of nsLTP1 from caraway seeds and its possible interaction with respective fatty acids using in silico approach. Our data indicated that the protein had anticancer and antioxidant activities and was thermally stable.

Synthesis and evaluation of the antioxidant and anti-tyrosinase activities of thiazolyl hydrazone derivatives and their application in the anti-browning of fresh-cut potato.

Tyrosinase is a key enzyme in the biosynthesis of melanin, which is responsible for the browning of foods as well as many skin disorders. In order to develop new anti-browning agents with dual antioxidant and anti-tyrosinase capacities, a series of 30 thiazolyl hydrazone derivatives were synthesized. Among the molecules prepared, 6 and 30 were found to be the most potent tyrosinase inhibitors with IC50 values ​​comparable to that of kojic acid. Interestingly, 6 also has the highest radical scavenging activity among the prepared molecules. The inhibition kinetics study indicated that 6 is a non-competitive inhibitor while 30 inhibits tyrosinase competitively. The anti-browning assay of fresh-cut potato slices revealed that 6 and 30 are potent anti-browning agents with a capacity as high as kojic acid. The mechanisms of free radical scavenging and tyrosinase inhibition have been fully investigated in silico using computational kinetics, molecular docking, and molecular dynamics simulations.

Overview of the Justicia Genus: Insights into Its Chemical Diversity and Biological Potential.

The genus Justicia has more than 600 species distributed in both hemispheres, in the tropics and temperate regions, and it is used in the treatment of numerous pathologies. This study presents a review of the biological activities of plant extracts and isolated chemical constituents of Justicia (ACANTHACEAE), identified in the period from May 2011 to August 2022. We analyzed over 176 articles with various biological activities and chemical compound descriptions present in the 29 species of Justicia. These have a variety of applications, such as antioxidant and antimicrobial, with alkaloids and flavonoids (e.g., naringenin) the most frequently identified secondary metabolites. The most observed species were Justicia gendarussa Burm., Justicia procumbens L., Justicia adhatoda L., Justicia spicigera Schltdl, and Justicia pectoralis Jacq. The frontier molecular orbitals carried out using density functional theory (M062X and basis set 6-311++G(d,p) indicate reactive sites for naringenin compound and a chemical reaction on phytomedicine activity. The energy gap (206.99 kcal/mol) and dimer solid state packing point to chemical stability. Due to the wide variety of pharmacological uses of these species, this review points toward the development of new phytomedicines.

Green Light-Triggerable Chemo-Photothermal Activity of Cytarabine-Loaded Polymer Carbon Dots: Mechanism and Preliminary In Vitro Evaluation.

Carbon-based nanostructures are attracting a lot of attention because of their very low toxicity, excellent visible light-triggered optical and photothermal properties, and intriguing applications. Currently, the development of multifunctional carbon-based nanostructures for a synergistic chemo-photothermal approach is a challenging topic for the advancement of cancer treatment. Here, we report an unprecedented example of photoresponsive carbon-based polymer dots (CPDs-PNM) obtained by a one-pot thermal process from poly(N-isopropylacrylamide) (PNIPAM) without using organic solvent and additional reagents. The CPDs-PNM nanostructures were characterized by spectroscopic techniques, transmission electron microscopy, and atomic force microscopy. The CPDs-PNM exhibited high photothermal conversion efficiency, lower critical solution temperature (LCST) behavior, and good cytarabine (arabinosyl cytosine, AraC) loading capacity (62.3%). The formation of a CPDs-PNM/AraC adduct and photothermal-controlled drug release, triggered by green light excitation, were demonstrated by spectroscopic techniques, and the drug-polymer interaction and drug release mechanism were well supported by modeling simulation calculations. The cellular uptake of empty and AraC-loaded CPDs-PNM was imaged by confocal laser scanning microscopy. In vitro experiments evidenced that CPDs-PNM did not affect the viability of neuroblastoma cells, while the CPDs-PNM/AraC adduct under light irradiation exhibited significantly higher toxicity than AraC alone by a combined chemo-photothermal effect.

Characterization of stenocephol from Seriphidium stenocephalum as potent HepG2 cell growth and glycogen phosphorylase inhibitor.

Plant-derived compounds represent an important source for developing innovative drugs. One of the widely distributed plants, especially in Afghanistan and Pakistan, Seriphidium stenocephalum, was investigated in this study to identify bioactive compounds. The plant extract was subjected to silica gel column chromatography, four phenolic acid derivatives were isolated, while stenocephol was obtained by ethyl acetate fraction. Stenocephol was subjected to experimental screening for anti-diabetic and anti-cancer activities, measuring its inhibitory potency against glycogen phosphorylase, and its cytotoxicity against HepG2 cells. Further insights into the mechanism of action of stenocephol were obtained from a computational investigation. Stenocephol showed a dose-dependent manner of inhibition against glycogen phosphorylase and HepG2 cells in the low micromolar range. Notably, coupling in vitro and computational investigation, we identified the natural product stenocephol as a possible anti-diabetic and anti-cancer agent, representing a possible starting point for developing novel therapeutics, enriching the armamentarium against the mentioned diseases.

Phytochemical analysis and molecular docking studies of two endemic varieties of Salvia sericeotomentosa.

The use of medicinal plants for treating various diseases dates back thousands of years and has been a part of many cultures around the world. Various parts of plants, including roots, leaves, and flowers, and their extracts have been used to develop remedies to cure different ailments like fever, pain, inflammation, infections, among others. In this research, the aerial parts of both Salvia varieties were extracted with ethanol and water to obtain infusion and decoction, separately. S. sericeotomentosa var. hatayica Celep & Dogan (SH) and Salvia sericeotomentosa Rech. f. var. sericeotomentosa (ST) plants were chemically analyzed for polar compounds using LC-HRMS for the first time. All SH and ST extracts were found to be very rich in rosmarinic acid, salvianolic acid B, hispidulin-7-O-glucoside, and caffeic acid. The study also investigated the antiinflammatory and carbonic anhydrase inhibition properties of the most abundant secondary metabolites extracted from SH and ST. In silico studies were conducted for the first time to explore the effects of these metabolites on TNF-α, iNOS, and human carbonic anhydrase isoenzymes (hCAI and hCAII). Salvianolic acid B should be considered a strong antiinflammatory agent and a carbonic anhydrase I and II inhibitors due to low binding energy scores with the tested enzymes (TNF-α: -12.391 kcal/mol), (iNOS: -7.547 kcal/mol), (hCAI: -7.877 kcal/mol), and (hCAII: -4.312 kcal/mol).

Valorization of Pimenta racemosa Essential Oils and Extracts: GC-MS and LC-MS Phytochemical Profiling and Evaluation of Helicobacter pylori Inhibitory Activity.

Pimenta racemosa is a commonly known spice used in traditional medicine to treat several ailments. In this study, comprehensive phytochemical profiling of the essential oils and methanol extracts of P. racemosa leaves and stems was performed, alongside assessing their potential Helicobacter pylori inhibitory activity in vitro and in silico. The essential oils were chemically profiled via GC-MS. Moreover, the methanol extracts were profiled using HPLC-PDA-ESI-MS/MS. The antibacterial activity of the essential oils and methanol extracts against H. pylori was determined by adopting the micro-well dilution method. GC-MS analysis unveiled the presence of 21 constituents, where eugenol represented the major component (57.84%) and (59.76%) in both leaves and stems of essential oils, respectively. A total of 61 compounds were annotated in both leaves and stems of P. racemosa methanolic extracts displaying richness in phenolic compounds identified as (epi)catechin and (epi)gallocatechin monomers and proanthocyanidins, hydrolyzable tannin derivatives (gallotannins), flavonoids, and phenolic acids. The stem essential oil showed the most promising inhibitory effects on H. pylori, exhibiting an MIC value of 3.9 µg/mL, comparable to clarithromycin with an MIC value of 1.95 µg/mL. Additionally, in silico molecular modeling studies revealed that decanal, eugenol, terpineol, delta-cadinene, and amyl vinyl showed potential inhibitory activity on H. pylori urease as demonstrated by high-fitting scores indicating good binding to the active sites. These findings indicate that P. racemosa comprises valuable phytochemical constituents with promising therapeutic effects, particularly the stem, an economic agro-industrial waste.

Discovery of putative inhibitors against main drivers of SARS-CoV-2 infection: Insight from quantum mechanical evaluation and molecular modeling.

SARS-CoV-2 triggered a worldwide medical crisis, affecting the world's social, emotional, physical, and economic equilibrium. However, treatment choices and targets for finding a solution to COVID-19's threat are becoming limited. A viable approach to combating the threat of COVID-19 is by unraveling newer pharmacological and therapeutic targets pertinent in the viral survival and adaptive mechanisms within the host biological milieu which in turn provides the opportunity to discover promising inhibitors against COVID-19. Therefore, using high-throughput virtual screening, manually curated compounds library from some medicinal plants were screened against four main drivers of SARS-CoV-2 (spike glycoprotein, PLpro, 3CLpro, and RdRp). In addition, molecular docking, Prime MM/GBSA (molecular mechanics/generalized Born surface area) analysis, molecular dynamics (MD) simulation, and drug-likeness screening were performed to identify potential phytodrugs candidates for COVID-19 treatment. In support of these approaches, we used a series of computational modeling approaches to develop therapeutic agents against COVID-19. Out of the screened compounds against the selected SARS-CoV-2 therapeutic targets, only compounds with no violations of Lipinski's rule of five and high binding affinity were considered as potential anti-COVID-19 drugs. However, lonchocarpol A, diplacol, and broussonol E (lead compounds) were recorded as the best compounds that satisfied this requirement, and they demonstrated their highest binding affinity against 3CLpro. Therefore, the 3CLpro target and the three lead compounds were selected for further analysis. Through protein-ligand mapping and interaction profiling, the three lead compounds formed essential interactions such as hydrogen bonds and hydrophobic interactions with amino acid residues at the binding pocket of 3CLpro. The key amino acid residues at the 3CLpro active site participating in the hydrophobic and polar inter/intra molecular interaction were TYR54, PRO52, CYS44, MET49, MET165, CYS145, HIS41, THR26, THR25, GLN189, and THR190. The compounds demonstrated stable protein-ligand complexes in the active site of the target (3CLpro) over a 100 ns simulation period with stable protein-ligand trajectories. Drug-likeness screening shows that the compounds are druggable molecules, and the toxicity descriptors established that the compounds demonstrated a good biosafety profile. Furthermore, the compounds were chemically reactive with promising molecular electron potential properties. Collectively, we propose that the discovered lead compounds may open the way for establishing phytodrugs to manage COVID-19 pandemics and new chemical libraries to prevent COVID-19 entry into the host based on the findings of this computational investigation.

Purification and characterization of enolase as a novel allergen in Platanus acerifolia pollen.

BACKGROUND: The pollen from Platanus acerifolia (P. acerifolia) is one of the main causes of allergic disorders. To date, only 4 allergens have been identified from this pollen. But previous studies showed that there still exist under-recognized allergens in it. The aim of this study was to comprehensively investigate the newly identified enolase (Pla a 6) as a novel allergen in the P. acerifolia pollen. METHODS: The natural (n) Pla a 6 was purified by combined chromatographic strategies. According to the identified internal peptides, the cDNA sequence encoding this allergen was matched from the mRNA-sequencing results of P. acerifolia pollen, which was further amplified and cloned. The recombinant (r) Pla a 6 was expressed and purified from E. coli. The allergenicity of this novel allergen was characterized by enzyme linked immunosorbent assay (ELISA), Western blot, inhibition ELISA, and basophil activation test (BAT). RESULTS: A novel allergen from P. acerifolia pollen, named as Pla a 6 was thoroughly studied, which contained an open reading frame of 1338 bp encoding 445 amino acids. The IgE-binding activity of nPla a 6 was initially proved by Western-blot, and a similar IgE-binding pattern to rPla a 6 was also exhibited. Moreover, the positivity for specific IgE against rPla a 6 was tested as 45.95% (17/37) by ELISA, and IgE binding to pollen extract could be inhibited up to 45.77% by 10 µg/ml of rPla a 6. The protein was also confirmed to activate patients' basophils. CONCLUSIONS: In this study, a novel allergen belonging to enolase family was comprehensively investigated and characterized through its natural and recombinant forms in P. acerifolia pollen. The study will contribute to the development of novel molecular-based diagnostic and therapeutic approaches for P. acerifolia pollen allergy.

Spectrum-Effect Relationship-Based Strategy Combined with Molecular Docking to Explore Bioactive Flavonoids from Sceptridium ternatum.

Sceptridium ternatum is a herbaceous plant with significant potential for pharmaceutical and cosmetic applications. In this study, we established a spectrum-effect relationship-based strategy to investigate the bioactive basis and tissue distribution in S. ternatum. First, a phytochemical analysis on the ethanol extracts from roots, stems, and leaves of S. ternatum was performed using the colorimetric method, high-performance liquid chromatography-ultraviolet (HPLC-UV), and high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOF-MS/MS). Then, radical scavenging assays and the lipopolysaccharide-stimulated RAW 264.7 cell model were used to estimate the antioxidant and anti-inflammatory activities, respectively. Spectrum-effect relationship analysis and molecular docking were further employed to evaluate the correlation between the phytochemical profile and anti-inflammatory activity. Our results demonstrate that S. ternatum leaves contained the most abundant flavonoids and exerted the best biological activities. Their IC50 values for scavenging 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) and 1,1-diphenyl-2-picrylhydrazyl radicals were 2.43 ± 0.13 and 5.36 ± 0.54 mg/mL, respectively. In lipopolysaccharide-stimulated RAW 264.7 cells, the leaf extract caused the greatest reduction in nitric oxide production (38.15%) and interleukin-6 release (110.86%). Spectrum-effect relationship analysis and molecular docking indicated that quercetin 3-O-rhamnoside-7-O-glucoside possessed high anti-inflammatory activity by binding with interleukin-6. In conclusion, S. ternatum is a rich source of bioactive flavonoids with potential for exploitation in the prevention and treatment of oxidative stress and inflammation-related pathologies.

Melaleuca rugulosa (Link) Craven Tannins: Appraisal of anti-inflammatory, radical scavenging activities, and molecular modeling studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Genus Melaleuca or tea tree species are well known to be an important source of biological active oils and extracts. The biological significance appears in their usage for treatment of several clinical disorder owing to their traditional uses as anti-inflammatory, antibacterial, antifungal, and cytotoxic activities. AIM OF THE STUDY: Our study aimed to investigate the metabolic profile of the M. rugulosa polyphenol-rich fraction along with determination of its anti-inflammatory potential, free radical scavenging and antiaging activities supported with virtual understanding of the mode of action using molecular modeling strategy. MATERIALS AND METHODS: The anti-inflammatory activity of the phenolic rich fraction was investigated through measuring its inhibitory activity against inflammatory mediators viz tumor necrosing factor receptor-2 (TNF-α) and cyclooxygenases 1/2 (COX-1/2) in a cell free and cell-based assays. Moreover, the radical scavenging activity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC) and ß-carotene assays, while the antiaging activity in anti-elastase, anti-collagenase, and anti-tyrosinase inhibitory assays. Finally, the biological findings were supported with molecular docking study using MOE software. RESULTS: The chromatographic purification of the polyphenol-rich fraction of Melaleuca rugulosa (Link) Craven afforded fourteen phytoconstituents (1-14). The anti-inflammatory gauging experiments demonstrated inhibition of inflammatory-linked enzymes COX-1/2 and the TNF-α at low µg/mL levels in the enzyme-based assays. Further investigation of the underlying mechanism was inferred from the quantification of protein levels and gene expression in the lipopolysaccharide (LPS)-activated murine macrophages (RAW264.7) in vitro model. The results revealed the reduction of protein synthesis of COX-1/2 and TNF-α with the down regulation of gene expression. The cell free in vitro radical scavenging assessment of the polyphenol-rich fraction revealed a significant DPPH reduction, peroxyl radicals scavenging, and ß-carotene peroxidation inhibition. Besides, the polyphenol-rich fraction showed a considerable inhibition of the skin aging-related enzymes as elastase, collagenase, and tyrosinase. Ultimately, the computational molecular modelling studies uncovered the potential binding poses and relevant molecular interactions of the identified polyphenols with their targeted enzymes. Particularly, terflavin C (8) which showed a favorable binding pose at the elastase binding pocket, while rosmarinic acid (14) demonstrated the best binding pose at the COX-2 catalytic domain. In short, natural polyphenols are potential candidates for the management of free radicals, inflammation, and skin aging related conditions. CONCLUSION: Natural polyphenols are potential candidates for the management of free radicals, inflammation, and skin aging related conditions.

An integrated approach for identifying the efficacy and potential mechanisms of TCM against atherosclerosis-Wu-Zhu-Yu decoction as a case study.

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) is a chronic disease that is associated with high morbidity. However, therapeutic approaches are limited. Wu-Zhu-Yu decoction (WZYD) is a well-known traditional Chinese medicine prescription that is traditionally used to treat headaches and vomiting. Modern studies have demonstrated the cardiotonic effects of WZYD. However, whether WZYD can alleviate AS and its underlying mechanisms remain unclear. AIM OF THE STUDY: This study aims to investigate the antiatherosclerotic efficacy of WZYD and illustrate its potential mechanisms using an integrated approach combining in vivo and in vitro assessments, including metabolomics, network pharmacology, cell experiments, and molecular docking analyses. MATERIALS AND METHODS: In this work, an atherosclerotic mouse model was established by administering a high-fat diet to apolipoprotein-E deficient (ApoE-/-) mice for twelve weeks. Meanwhile, the mice were intragastrically administered WZYD at different dosages. Efficacy evaluation was performed through biochemical and histopathological assessments. The potential active constituents, metabolites, and targets of WZYD in atherosclerosis were predicted by metabolomics combined with network pharmacology analysis, the constituents and targets were further assessed through cell experiments and molecular docking analysis. RESULTS: WZYD decreased the lipid levels in serum, reduced the areas of aortic lesions, and attenuated intimal thickening, which had antiatherosclerotic effects in ApoE-/- mice. Metabolomics and network pharmacology approach revealed that the ten constituents (6-shogaol, evodiamine, isorhamnetin, quercetin, beta-carotene, 8-gingerol, kaempferol, 6-paradol, 10-gingerol, and 6-gingerol) of WZYD affected 24 metabolites by acting on the candidate targets, thus resulting in changes in five metabolic pathways (sphingolipid metabolism; glycine, serine and threonine metabolism; arachidonic acid metabolism; tryptophan metabolism; and fatty acid biosynthesis pathway). Cell experiments indicated that the ten key compounds showed antiproliferative effects on the vascular smooth muscle cell. Moreover, the key compounds exhibited direct interactions with the key targets, as assessed by molecular docking analysis. CONCLUSION: This study revealed that WZYD exerted therapeutic effects on atherosclerosis, and the potential mechanisms were elucidated. Furthermore, it offered a powerful integrated strategy for studying the efficacy of traditional Chinese medicine and exploring its active components and possible mechanisms.