Investigation of phytochemicals isolated from selected Saudi medicinal plants as natural inhibitors of SARS CoV-2 main protease: In vitro, molecular docking and simulation analysis.

The escalation of many coronavirus variants accompanied by the lack of an effective cure has motivated the hunt for effective antiviral medicines. In this regard, 18 Saudi Arabian medicinal plants were evaluated for SARS CoV-2 main protease (Mpro) inhibition activity. Among them, Terminalia brownii and Acacia asak alcoholic extracts exhibited significant Mpro inhibition, with inhibition rates of 95.3 % and 95.2 %, respectively, at a concentration of 100 µg/mL. Bioassay-guided phytochemical study for the most active n-butanol fraction of T. brownii led to identification of eleven compounds, including two phenolic acids (1, and 2), seven hydrolysable tannins (3-10), and one flavonoid (11) as well as four flavonoids from A. asak (12-15). The structures of the isolated compounds were established using various spectroscopic techniques and comparison with known compounds. To investigate the chemical interactions between the identified compounds and the target Mpro protein, molecular docking was performed using AutoDock 4.2. The findings identified compounds 4, 5, 10, and 14 as the most potential inhibitors of Mpro with binding energies of -9.3, -8.5, -8.1, and -7.8 kcal mol-1, respectively. In order to assess the stability of the protein-ligand complexes, molecular dynamics simulations were conducted for a duration of 100 ns, and various parameters such as RMSD, RMSF, Rg, and SASA were evaluated. All selected compounds 4, 5, 10, and 14 showed considerable Mpro inhibiting activity in vitro, with compound 4 being the most powerful with an IC50 value of 1.2 µg/mL. MM-GBSA free energy calculations also revealed compound 4 as the most powerful Mpro inhibitor. None of the compounds (4, 5, 10, and 14) display any significant cytotoxic activity against A549 and HUVEC cell lines.

New terpenic and phenolic compounds from Suaeda monoica reverse oxidative and apoptotic damages in human endothelial cells.

Elevation in hyperglycemia-associated methylglyoxal level can trigger vascular endothelial cells oxidative stress and apoptosis. The present work assesses the cell proliferative, anti-oxidative and anti-apoptotic potential of Suaeda monoica derived four new terpenes: a norsesquaterpenol (normonisesquaterpenol), a monocyclic triterpenoid (suaedanortriterpene dione), an aromatic monoterpenic ester and a labdane-type norditerpenic xyloside as well as two new phenols: an alkylated ß-naphthol and a ß-methoxy naphthalene in cultured human umbilical vein endothelial cells (HUVEC). Of these, suaedanortriterpenedione (53.7%), normonisesquaterpenol (51.4%) and norditerpenic xyloside (48%) showed the most promising cell proliferative activities compared to others. Moreover, normonisesquaterpenol, norditerpenic xyloside and suaedanortriterpenedione efficiently reversed the oxidative and apoptotic cell damage via downregulation of capase-3/7 by 44.3%, 42.2% and 39.4%, respectively against dichlorofluorescin, whereas by 46.2%, 43.5% and 42.5%, respectively against methylglyoxal. Aminoguanidine, the reference drug inhibited caspase-3/7 activity by 56.2% and 54.7% through attenuation of dichlorofluorescin and methylglyoxal, respectively. Further in silico molecular docking analysis revealed formation of stable complexes between the tested compounds and caspase-3/7. Conclusively, we for the first time demonstrate the growth stimulatory, anti-oxidative and anti-apoptotic salutations of S. monoica derived novel compounds in human endothelial cells. This warrants their further assessment as vascular cell protective and rejuvenating therapeutics, especially in hyperglycemic conditions.

Impact of Different Extraction Methods on Furanosesquiterpenoids Content and Antibacterial Activity of Commiphora myrrha Resin.

The oleo-gum-resin of Commiphora myrrha is one of the most known natural antimicrobial agents, mainly due to its furanosesquiterpenes. A validated method based on sample extraction by matrix solid-phase dispersion (MSPD) followed by high-performance column chromatography (HPLC) determination is applied to analyze two furanosesquiterpenoids, namely, 2-methoxyfuranodiene (CM-1) and 2-acetoxyfuranodiene (CM-2), existing in C. myrrha. The trial parameters that controlled the extraction prospective were studied and optimized. These include the nature of dispersant, mass ratio of sample to the dispersant, and the volume of elution solvent. A comparative antimicrobial study that used the Minimum Inhibitory Concentration Assay (MIC) method between MSPD, ultrasonic, and Soxhlet of myrrh extracts was also conducted. The optimal MSPD parameters used were (i) 15 mL of methanol applied as elution solvent; (ii) silica gel/sample mass at a 2 : 1 ratio; and (iii) a dispersing sorbent selected as silica gel. Technique retrievals were regulated from 96.87% to 100.54%, with relative standard deviations (RSDs) from 1.24% to 4.45%. Commiphora myrrha-MSPD (CM-MSPD) extract showed the highest antibacterial activity against gram-positive and gram-negative bacteria (156.25 µg/mL and 312.5 µg/mL, respectively) and antifungal activity (156.25 µg/mL). Yields acquired through the MSPD technique were larger than yields from other extraction techniques (sonication and traditional reflux extraction methods) with less consumption of time, sample, and solvent. The mode of antibacterial action of CM-1 and CM-2 was elucidated by performing molecular docking with bacterial DNA gyrase. Both the compounds interacted with key residues of DNA gyrase.

Preparation, characterization, and in vitro-in silico biological activities of Jatropha pelargoniifolia extract loaded chitosan nanoparticles.

Jatropha pelargoniifolia (JP) is a medicinal plant that is widely used in traditional medicine owing to its broad range of therapeutic activities. Despite its promising pharmacological activities, the use of plant extracts has several limitations which can be overcome using pharmaceutical nanotechnology. The aim of this study was to systematically investigate the effect of nanoencapsulation on the antimicrobial and anticancer activities of JP extract. JP-loaded chitosan nanoparticles (JP-CSNPs) were prepared using the ionic gelation method and characterized in terms of size, polydispersity index, zeta potential, encapsulation efficiency, and release profile. Transmission electron microscopy was used to observe the morphology of the nanoparticles. The mean particle size, zeta potential, and encapsulation efficiency of optimized JP-CSNPs were 185.5 nm, 44 mV, and 78.5%, respectively. The release profile of the JP-CSNPs was mainly dependent on the pH of the surrounding medium, and the JP extract was released in a controlled manner over time. The total phenolic and flavonoid contents in JP extract were 191.8 mg GAE/g extract and 51.4 mg of QE/g extract, respectively. The results of a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay showed that JP-CSNPs retained the antioxidant activity of unencapsulated JP extract. JP-CSNPs also exhibited higher antimicrobial activity against gram-positive bacteria than against gram-negative bacteria, and their minimum inhibitory concentration was 1.6-fold lower than that of blank nanoparticles, indicating the synergy between JP extract and nanoparticles. In vitro cytotoxicity studies using A549 human lung adenocarcinoma cells revealed that JP-CSNPs had a 2-fold lower half-maximal inhibitory concentration than free extract. Molecular docking analyses revealed that the active phytoconstituent of JP extract, linarin, binds strongly to the active sites of bacterial DNA gyrase B and human DNA topoisomerase IIα and thus, may inhibit their activities. Computational analysis results supported the in vitro finding that JP-CSNPs act as an anticancer and antimicrobial agent. Taken together, the results of this study highlighted the advantages of using CSNPs as a nanocarrier for herbal extracts, thus providing a potential strategy for improving plant-based therapeutics.

Identification of natural compounds as potent inhibitors of SARS-CoV-2 main protease using combined docking and molecular dynamics simulations.

Coronavirus disease 2019 (COVID-19) has emerged from China and globally affected the entire population through the human-to-human transmission of a newly emerged virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 encodes several proteins that are essential for multiplication and pathogenesis. The main protease (Mpro or 3CLpro) of SARS-CoV-2 plays a central role in its pathogenesis and thus is considered as an attractive drug target for the drug design and development of small-molecule inhibitors. We have employed an extensive structure-based high-throughput virtual screening to discover potential natural compounds from the ZINC database which could inhibit the Mpro of SARS-CoV-2. Initially, the hits were selected on the basis of their physicochemical and drug-like properties. Subsequently, the PAINS filter, estimation of binding affinities using molecular docking, and interaction analyses were performed to find safe and potential inhibitors of SARS-CoV-2 Mpro. We have identified ZINC02123811 (1-(3-(2,5,9-trimethyl-7-oxo-3-phenyl-7H-furo[3,2-g]chromen-6-yl)propanoyl)piperidine-4-carboxamide), a natural compound bearing appreciable affinity, efficiency, and specificity towards the binding pocket of SARS-CoV-2 Mpro. The identified compound showed a set of drug-like properties and preferentially binds to the active site of SARS-CoV-2 Mpro. All-atom molecular dynamics (MD) simulations were performed to evaluate the conformational dynamics, stability and interaction mechanism of Mpro with ZINC02123811. MD simulation results indicated that Mpro with ZINC02123811 forms a stable complex throughout the trajectory of 100 ns. These findings suggest that ZINC02123811 may be further exploited as a promising scaffold for the development of potential inhibitors of SARS-CoV-2 Mpro to address COVID-19.

Corrigendum to "New terpenic and phenolic compounds from Suaeda monoica reverse oxidative and apoptotic damages in human endothelial cells". [Saudi Pharm. J. 29(10) (2021) 1102-1111].

[This corrects the article DOI: 10.1016/j.jsps.2021.08.007.].

GABA reverses salt-inhibited photosynthetic and growth responses through its influence on NO-mediated nitrogen-sulfur assimilation and antioxidant system in wheat.

Gamma-aminobutyric acid (GABA) is a newly recognized signaling molecule participating in physiological processes, growth, and development of plants under optimal and stressful environments. In the present reported research, we investigated the role of GABA in imparting salt stress tolerance in wheat (Triticum aestivum L.). Exposure of wheat plants to 100 mM NaCl resulted in increased oxidative stress, glucose content, nitric oxide (NO) production together with reduced growth and photosynthetic traits of plants. Contrarily, GABA application improved nitrogen (N) metabolism, sulfur (S) assimilation, ion homeostasis, growth and photosynthesis under salt stress. Additionally, GABA mitigated oxidative stress induced by salt stress with the increased ascorbate-glutathione cycle and proline metabolism. The study with NO inhibitor, c-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide] in GABA experiment suggested that the impact of GABA on improvement of growth and photosynthesis under salt stress was mediated by NO and influenced N and S assimilation and antioxidant systems. The results suggested that the GABA has a significant potential in reversing the salt stress response in wheat plants, and GABA-mediated signals are manifested through NO.

Siphonocholin isolated from red sea sponge Siphonochalina siphonella attenuates quorum sensing controlled virulence and biofilm formation.

Increasing incidence of multi-drug resistant bacterial pathogens, especially in clinical settings, has been developed into a grave health situation. The drug resistance problem demands the necessity for alternative unique therapeutic policies. One such tactic is targeting the quorum sensing (QS) controlled virulence and biofilm production. In this study, we evaluated a marine steroid Siphonocholin (Syph-1) isolated from Siphonochalina siphonella against Chromobacterium violaceum (CV) 12472, Pseudomonas aeruginosa (PAO1), Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii (BAA) for biofilm and pellicle formation inhibition, and anti-QS property. MIC of Syph-1 against MRSA, CV, PAO1 was found as 64 µg/mL and 256 µg/mL against BAA. At selected sub-MICs, Syph-1 significantly (P ≤ 0.05) decreased the production of QS regulated virulence functions of CV12472 (violacein) and PAO1 [elastase, total protease, pyocyanin, chitinase, exopolysaccharides, and swarming motility]. The Syph-1 significantly decreased (p = 0.005) biofilm formation ability of tested bacterial pathogens, at sub-MIC level (PAO1 > MRSA > CV > BAA) and pellicle formation in A. baumannii (at 128 µg/mL). Molecular docking and simulation results indicated that Siph-1 was bound at the active site of BfmR N-terminal domain with high affinity. This study highlights the anti-QS and anti-biofilm activity of Syph-1 against bacterial pathogens reflecting its broad spectrum anti-infective potential.

Molecular interaction of tea catechin with bovine ß-lactoglobulin: A spectroscopic and in silico studies.

Polyphenols has attained pronounced attention due to their beneficial values of health and found to prevent several chronic diseases. Here, we elucidated binding mechanism between frequently consumed polyphenol "tea catechin" and milk protein bovine beta-lactoglobulin (ß-Lg). We investigated the conformational changes of ß-Lg due to interaction with catechin using spectroscopic and in silico studies. Fluorescence quenching data (Stern-Volmer quenching constant) revealed that ß-Lg interacted with catechin via dynamic quenching. Thermodynamic data revealed that the interaction between ß-Lg and catechin is endothermic and spontaneously interacted mainly through hydrophobic interactions. The UV-Vis absorption and far-UV circular dichroism (CD) spectroscopy exhibited that the tertiary as well as secondary structure of ß-Lg distorted after interaction with catechin. Molecular docking and simulation studies also confirm that catechin binds at the central cavity of ß-Lg with high affinity (~105 M-1) and hydrophobic interactions play significant role in the formation of a stable ß-Lg-catechin complex.

Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: Cell culture and molecular docking study.

Despite high anti-HBV efficacies, while the nucleoside analogs (e.g., lamivudine) lead to the emergence of drug-resistance, interferons (e.g., IFN-α causes adverse side-effects. Comparatively, various natural or plant products have shown similar or even better efficacy. Hence, new antiviral strategies must focus not only on synthetic molecules but also on potential natural compounds. In this report, we have combined the in vitro cell culture and in silico molecular docking methods to assess the novel anti-HBV activity and delineate the inhibitory mechanism of selected plant-derived pure compounds of different classes. Of the tested (2.5-50 µg/ml) twelve non-cytotoxic compounds, ten (10 µg/ml) were found to maximally inhibit HBsAg production at day 5. Compared to quercetin (73%), baccatin III (71%), psoralen (67%), embelin (65%), menisdaurin (64%) and azadirachtin (62%) that showed high inhibition of HBeAg synthesis, lupeol (52%), rutin (47%), ß-sitosterol (43%) and hesperidin (41%) had moderate efficacies against HBV replication. Further assessment of quercetin in combination with the highly active compounds, enhanced its anti-HBV activity up to 10%. Being the most important drug target, a 3-D structure of HBV polymerase (Pol/RT) was modeled and docked with the active compounds, including lamivudine as standard. Docking of lamivudine indicated strong interaction with the modeled HBV Pol active-site residues that formed stable complex (∆G = -5.2 kcal/mol). Similarly, all the docked antiviral compounds formed very stable complexes with HBV Pol (∆G = -6.1 to -9.3 kcal/mol). Taken together, our data suggest the anti-HBV potential of the tested natural compounds as novel viral Pol/RT inhibitors.