Computational docking investigation of phytocompounds from bergamot essential oil against Serratia marcescens protease and FabI: Alternative pharmacological strategy.

The rapid development of multi-drug resistant (MDR) pathogens adds urgency to search for novel and safe drugs having promising action on new and re-emerging infectious pathogens. Serratia marcescens is an MDR pathogen that causes several-healthcare associated infections. Curbing bacterial virulence, rather than inhibiting its growth, is a promising strategy to diminish the pathogenesis of infectious bacteria, reduce the development of antimicrobial resistance, and boost the host immune power to eradicate infections. Bergamot essential oil (BEO) is a remarkable source of promising therapeutics against pathogens. Therefore, the present investigation aimed to analyze the major phytocompounds from BEO against S. marcescens virulent proteins using in silico studies. The analysis of BEO phytocompounds was achieved by Gas chromatography-mass spectrometry (GC-MS) method. The molecular docking was carried out using the SP and XP docking protocol of the Glide program. The drug-likeness and pharmacokinetics properties (ADMET properties) were analyzed with SwissADME and pkCSM server. The results revealed that the major compounds present in BEO are Linalool (8.17%), D-Limonene (21.26%), and Linalyl acetate (26.91%). Molecular docking analysis revealed that these compounds docked strongly within the binding cavities of Serratia protease and FabI model which in turn curb the pathogenesis of this bacteria. Linalool interacted with the Serratia protease and FabI with a binding energy of - 3.130 kcal/mol and - 3.939 kcal/mol, respectively. Based on the pharmacokinetics findings all lead BEO phytocompounds appear to be promising drug candidates. Overall, these results represent a significant step in the development of plant-based compounds as a promising inhibitor of the virulent proteins of the MDR S. marcescens.

Antioxidant, anti-quorum sensing, biofilm inhibitory activities and chemical composition of Patchouli essential oil: in vitro and in silico approach.

The interest in naturally occurring essential oils from medicinal plants has increased extremely over the last decade markedly because they possess antimicrobial and antioxidant protective properties against different chronic diseases. Extensive survival of drug-resistant infectious bacteria depends on quorum sensing (QS) signaling network which raises the need for alternative antibacterial compounds. The aim of this study was to examine the phytochemical compounds of patchouli essential oil (PEO) and to assess its antioxidant activity. Antioxidant studies estimated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method showed that the PEO has effective antioxidant activity (IC50 19.53 µg/mL). QS inhibitory activity of PEO was examined by employing the biosensor strain, Chromobacterium violaceum CV12472. At sub-lethal concentrations, PEO potentially reduced the QS regulated violacein synthesis in CV12472 without inhibiting its cell proliferation. Moreover, it also effectively reduced the production of some QS regulated virulence factors and biofilm development in P. aeruginosa PAO1 without hindering its growth. Phytochemical analysis of PEO was done by GC/MS technique. Molecular docking of PEO major compounds with QS (LasR and FabI) and biofilm regulator proteins (MvfR and Sialidase) of PAO1 was evaluated. These phytocompounds showed potential hydrogen binding interactions with these proteins. The overall results, in vitro and in silico, suggest that PEO could be applied as biocontrol agent against antibiotic resistance pathogens. Communicated by Ramaswamy H. Sarma.

Biflavonoids from Rhus succedanea as probable natural inhibitors against SARS-CoV-2: a molecular docking and molecular dynamics approach.

The recent outbreak of SARS-CoV-2 has quickly become a worldwide pandemic and generated panic threats for both the human population and the global economy. The unavailability of effective vaccines or drugs has enforced researchers to hunt for a potential drug to combat this virus. Plant-derived phytocompounds are of applicable interest in the search for novel drugs. Bioflavonoids from Rhus succedanea are already reported to exert antiviral activity against RNA viruses. SARS-CoV-2 Mpro protease plays a vital role in viral replication and therefore can be considered as a promising target for drug development. A computational approach has been employed to search for promising potent bioflavonoids from Rhus succedanea against SARS-CoV-2 Mpro protease. Binding affinities and binding modes between the biflavonoids and Mpro enzyme suggest that all six biflavonoids exhibit possible interaction with the Mpro catalytic site (-19.47 to -27.04 kcal/mol). However, Amentoflavone (-27.04 kcal/mol) and Agathisflavone (-25.87 kcal/mol) interact strongly with the catalytic residues. Molecular dynamic simulations (100 ns) further revealed that these two biflavonoids complexes with the Mpro enzyme are highly stable and are of less conformational fluctuations. Also, the hydrophobic and hydrophilic surface mapping on the Mpro structure as well as biflavonoids were utilized for the further lead optimization process. Altogether, our findings showed that these natural biflavonoids can be utilized as promising SARS-CoV-2 Mpro inhibitors and thus, the computational approach provides an initial footstep towards experimental studies in in vitro and in vivo, which is necessary for the therapeutic development of novel and safe drugs to control SARS-CoV-2. Communicated by Ramaswamy H. SarmaResearch highlightsRhus succedanea biflavonoids have antiviral activity.The molecular interactions and molecular dynamics displayed that all six biflavonoids bound with a good affinity to the same catalytic site of Mpro.The compound Amentoflavone has a strong binding affinity (-27.0441 kcal/mol) towards Mpro.The binding site properties of SARS-CoV-2-Mpro can be utilized in a novel discovery and lead optimization of the SARS-CoV-2-Mpro inhibitor.

Phytoremediation of arsenic from the contaminated soil using transgenic tobacco plants expressing ACR2 gene of Arabidopsis thaliana.

We have cloned, characterized and transformed the AtACR2 gene (arsenic reductase 2) of Arabidopsis thaliana into the genome of tobacco (Nicotiana tabacum, var Sumsun). Our results revealed that the transgenic tobacco plants are more tolerant to arsenic than the wild type ones. These plants can grow on culture medium containing 200µM arsenate, whereas the wild type can barely survive under this condition. Furthermore, when exposed to 100µM arsenate for 35days the amount of arsenic accumulated in the shoots of transgenic plants was significantly lower (28µg/g d wt.) than that found in the shoots of non-transgenic controls (40µg/g d wt.). However, the arsenic content in the roots of transgenic plants was significantly higher (2400µg/g d. wt.) than that (2100µg/g d. wt.) observed in roots of wild type plants. We have demonstrated that Arabidopsis thaliana AtACR2 gene is a potential candidate for genetic engineering of plants to develop new crop cultivars that can be grown on arsenic contaminated fields to reduce arsenic content of the soil and can become a source of food containing no arsenic or exhibiting substantially reduced amount of this metalloid.

In silico and in vivo studies of molecular structures and mechanisms of AtPCS1 protein involved in binding arsenite and/or cadmium in plant cells.

This paper reports a continuation of our previous research on the phytochelatin synthase1 (PCS1) gene involved in binding and sequestration of heavy metals or metalloids in plant cells. Construction of a 3D structure of the Arabidopsis thaliana PCS1 protein and prediction of gene function by employing iterative implementation of the threading assembly refinement (I-TASSER) revealed that PC ligands (3GC-gamma-glutamylcysteine) and Gln50, Pro53, Ala54, Tyr55, Cys56, Ile102, Gly161, His162, Phe163, Asp204 and Arg211 residues are essential for formation of chelating complex with cadmium (Cd²âº) or arsenite (AsIII). This finding suggests that the PCS1 protein might be involved in the production of the enzyme phytochelatin synthase, which might in turn bind, localize, store or sequester heavy metals in plant cells. For validation of the in silico results, we included a T-DNA tagged mutant of Arabidopsis thaliana, SAIL_650_C12, (mutation in AtPCS1 gene) in our investigation. Furthermore, using reverse transcriptase PCR we confirmed that the mutant does not express the AtPCS1 gene. Mutant plants of SAIL_650_C12 were exposed to various amounts of cadmium (Cd²âº) and arsenite (AsIII) and the accumulation of these toxic metals in the plant cells was quantified spectrophotometrically. The levels of Cd²âº and AsIII accumulation in the mutant were approximately 2.8 and 1.6 times higher, respectively, than that observed in the wild-type controlled plants. We confirmed that the results obtained in in silico analyses complement those obtained in in vivo experiments.

Diverse pathological implications of YKL-40: answers may lie in 'outside-in' signaling.

The developing paradigms about YKL-40, a member of the "mammalian chitinase-like proteins", from across the globe, project it as a vital parameter for the detection of disease onset and progression. It is expressed and secreted by cancer cells of different origins along with a variety of non-malignant cells including inflammatory and structural cells. Numerous studies demonstrate that YKL-40 over-expression is associated with increased patient mortality though the cellular receptors responsible for mediating these effects have not yet been identified. The putative YKL-40 ligands are thought to be carbohydrate structures, since it is capable of binding chitin, chito-oligosaccharides and heparin. Binding of collagen to YKL-40, identified it as the only non-carbohydrate extracellular matrix (ECM) ligand for YKL-40. Our broad understanding of YKL-40 as a versatile biomarker and its involvement in activating several signaling pathways make us anticipate that its specific receptors/binding partners may exist on the cell surface also. The cell surface heparan sulfate (HS) moieties seem to be the potential candidates for this role, suggesting that it could interact with HS-proteoglycans. It is recommended to clearly delineate YKL-40-mediated signaling mechanisms before promoting the YKL-40 know-how for translational research, in both diagnostic and therapeutic applications. The present review provides an overview of YKL-40 as a versatile biomarker, discussing the related pathological mechanisms and aims to reassess and unify the already proposed diverse hypotheses in YKL-40-regulated signaling mechanisms.