Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough ...evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.
Polo-like kinase-1 (PLK-1) plays a key role in cell cycle progression during mitosis. Overexpression/dysfunction of PLK-1 is directly associated with cancerous transformation and has been reported in ...different cancer types. Here, we employed high throughput virtual screening and molecular docking to screen Selleck's natural compound library against PLK-1 kinase domain. We have identified eight bioactive compounds (Apigenin, Dihydromyricetin, Diosmetin, Hesperidin, Hesperitin, Naringenin, Phlorizi, and Quercetin) as the potential inhibitors of PLK-1. Further investigation through Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations and 15 ns molecular dynamics simulation revealed that hesperidin formed the most stable complex with PLK-1 kinase domain. Altogether, our results indicate that hesperidin interacted strongly with the key residues of the PLK-1 active site (such as Leu59, Lys61, Lys82, Cys133, Asn181, Asp194, Leu59, Cys67, Ala80, Val114, Leu130, Leu132, Cys133, Leu139, Phe183, and Phe195) through hydrogen bonding and hydrophobic interactions. The Hesperidin-PLK-1 complex was stabilized by Gibb's free energy of −13.235 kcal/mol which corresponded to the binding affinity of 5.095 × 109 M−1. This is the first study wherein hesperidin has been identified as a potential inhibitor of PLK-1. Further design and optimization of the hesperidin scaffold as an inhibitor of PLK-1 kinase domain is highly recommended.
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In recent years, the demand for novel antifungal therapies has increased several- folds due to its potential to treat severe biofilm-associated infections. Biofilms are made by the sessile ...microorganisms attached to the abiotic or biotic surfaces, enclosed in a matrix of exopolymeric substances. This results in new phenotypic characteristics and intrinsic resistance from both host immune response and antimicrobial drugs.
biofilm is a complex association of hyphal cells that are associated with both abiotic and animal tissues. It is an invasive fungal infection and acts as an important virulent factor. The challenges linked with biofilm-associated diseases have urged scientists to uncover the factors responsible for the formation and maturation of biofilm. Several strategies have been developed that could be adopted to eradicate biofilm-associated infections. This article presents an overview of the role of
biofilm in its pathogenicity, challenges it poses and threats associated with its formation. Further, it discusses strategies that are currently available or under development targeting prostaglandins, quorum-sensing, changing surface properties of biomedical devices, natural scaffolds, and small molecule-based chemical approaches to combat the threat of
biofilm. This review also highlights the recent developments in finding ways to increase the penetration of drugs into the extracellular matrix of biofilm using different nanomaterials against
.
Nitric oxide (NO) is a hormone that connects numerous reactions in plant cells under normal and environmental stress conditions. The application of 100 µM NO as sodium nitroprusside (SNP; NO donor) ...applied individually or in combination with N or S in different combinations (i.e. 100 mg N or S kg−1 soil applied at the time of sowing 100 N + 100S0d or with split, 50 mg N or S kg−1 soil at the time of sowing and similar dose at 20 d after sowing 50 N + 50S0d + 50 N + 50S20d) was tested to alleviate salt stress in mustard (Brassica juncea L.). Application of 100 µM NO plus split application of N and S more significantly promoted stomatal behavior, photosynthetic and growth performance in the absence of salt stress and maximally alleviated effects of salt stress through increased N‐ and S‐use efficiency, proline and antioxidant system. The combined application of N and S at the time of sowing was lesser effective in promoting photosynthesis and growth under salt or no salt stress conditions in presence or absence of NO. The study suggests that salt stress effects on the photosynthetic performance are mitigated more efficiently when NO was applied together with the split application of N and S given at two stages, and the photosynthetic activity was promoted under salt stress through increased N and S assimilation and antioxidant system. This strategy may be adopted in agricultural system for overcoming salt stress effects on performance of mustard.
Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that works under acute transcriptional control by several stimuli, including serum and glucocorticoids. It plays a ...significant role in the cancer progression and metastasis, as it regulates inflammation, apoptosis, hormone release, neuro-excitability, and cell proliferation. SGK1 has recently been considered as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In the present study, we have performed structure-based virtual high-throughput screening of natural compounds from the ZINC database to find potential inhibitors of SGK1. Initially, hits were selected based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and other drug-like properties. Afterwards, PAINS filter, binding affinities estimation, and interaction analysis were performed to find safe and effective hits. We found four compounds bearing appreciable binding affinity and specificity towards the binding pocket of SGK1. The docking results were complemented by all-atom molecular dynamics simulation for 100 ns, followed by MM/PBSA, and principal component analysis to investigate the conformational changes, stability, and interaction mechanism of SGK1 in-complex with the selected compound ZINC00319000. Molecular dynamics simulation results suggested that the binding of ZINC00319000 stabilizes the SGK1 structure, and it leads to fewer conformational changes. In conclusion, the identified compound ZINC00319000 might be further exploited as a scaffold to develop promising inhibitors of SGK1 for the therapeutic management of associated diseases, including cancer.
The continuously increasing incidence rates of cancer and infectious diseases are open threats to the sustainable survival of animals and humans. In the last two decades, the demands of nanomaterials ...as modern therapeutic agents have increased. In this study, biogenic zinc oxide nanoparticles (ZnO NPs) were developed from aqueous
leaf extract (POLE) and characterized using modern methods and tools, such as electron microscopy, X-ray diffraction, energy dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy and UV-vis spectroscopy, which indicated the formation of very pure, spherical NPs approximately 90 nm in size. The anticancer activity of the ZnO NPs was evaluated by MTT and neutral red uptake (NRU) assays in MCF-7, HepG2 and A-549 cells at different doses (1, 2, 5, 10, 25, 50, 100 μg ml
). Moreover, the morphology of the treated cancer cells was examined by phase contrast microscopy. The results suggest that the synthesized ZnO NPs inhibited the growth of the cells when applied a concentration from 50-100 μg ml
. Moreover, the biogenic ZnO NPs were analysed as an antimicrobial agent against pathogenic bacteria. The highest antibacterial activity was observed against Gram-positive
(26 nm) and Gram-negative
(24 mm) at 50 μg per well. Complete bacterial growth (100%) vanished 100% upon treatment with ZnO NPs at 85 μg ml
. Overall, POLE mediated derived biogenic ZnO NPs could serve as a significant anticancer and antimicrobial agent and be used in the development of novel drugs and skin care products.
Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation ...of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic acid, and ferulic acid for their potential to inhibit the activity of CDK6. Molecular docking and fluorescence binding studies revealed appreciable binding affinities of these compounds to the CDK6. Among them, EA shows the highest binding affinity for CDK6, and thus a molecular dynamics simulation study of 200 ns was performed to get deeper insights into the binding mechanism and stability of the CDK6-EA complex. Fluorescence binding studies revealed that EA binds to the CDK6 with a binding constant of
= 10
M
and subsequently inhibits its enzyme activity with an IC
value of 3.053 µM. Analysis of thermodynamic parameters of CDK6-EA complex formation suggested a hydrophobic interaction driven process. The treatment of EA decreases the colonization of cancer cells and induces apoptosis. Moreover, the expression of CDK6 has been downregulated in EA-treated human breast cancer cell lines. In conclusion, this study establishes EA as a potent CDK6 inhibitor that can be further evaluated in CDK6 directed anticancer therapies.
Pollination plays a significant role in the agriculture sector and serves as a basic pillar for crop production. Plants depend on vectors to move pollen, which can include water, wind, and animal ...pollinators like bats, moths, hoverflies, birds, bees, butterflies, wasps, thrips, and beetles. Cultivated plants are typically pollinated by animals. Animal-based pollination contributes to 30% of global food production, and bee-pollinated crops contribute to approximately one-third of the total human dietary supply. Bees are considered significant pollinators due to their effectiveness and wide availability. Bee pollination provides excellent value to crop quality and quantity, improving global economic and dietary outcomes. This review highlights the role played by bee pollination, which influences the economy, and enlists the different types of bees and other insects associated with pollination.
The ionic liquids have special features and, hence, called as liquid electrolytes, ionic melts, ionic glasses, fused salts, liquid salts, ionic fluids, designer solvents, green, and future solvents. ...Achiral and chiral ionic liquids have been used in enantioseparations of a variety of racemates in high-performance liquid chromatography and capillary electrophoresis. Chiral ionic liquids have received a good reputation in high-performance liquid chromatography and capillary electrophoresis because of their astonishing properties. This review discusses the applications of achiral and chiral ionic liquids in enantioseparations in high-performance liquid chromatography and capillary electrophoresis. In addition, the attempts were also made to emphasize the toxicity and future prospective of these ionic liquids. Additionally, the attempts were made to discuss the chiral recognition mechanism.
The bacteria expressing New Delhi Metallo-β-lactamase-1 (NDM-1) can hydrolyze all β-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination ...of gene
(produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-β-lactam ring-containing inhibitors of NDM-1 by applying a high-throughput virtual screening of lead-like subset of ZINC database. The screened compounds were followed for the molecular docking, the molecular dynamics simulation, and then enzyme kinetics assessment. The adopted screening procedure funnels out five novel inhibitors of NDM-1 including ZINC10936382, ZINC30479078, ZINC41493045, ZINC7424911, and ZINC84525623. The molecular mechanics-generalized born surface area and molecular dynamics (MD) simulation showed that ZINC84525623 formed the most stable complex with NDM-1. Furthermore, analyses of the binding pose after MD simulation revealed that ZINC84525623 formed two hydrogen bonds (electrostatic and hydrophobic interaction) with key amino acid residues of the NDM-1 active site. The docking binding free energy and docking binding constant for the ZINC84525623 and NDM-1 interaction were estimated to be -11.234 kcal/mol, and 1.74 × 10⁸ M
respectively. Steady-state enzyme kinetics in the presence of ZINC84525623 show the decreased catalytic efficiency (i.e.,
/
) of NDM-1 on various antibiotics. The findings of this study would be helpful in identifying novel inhibitors against other β-lactamases from a pool of large databases. Furthermore, the identified inhibitor (ZINC84525623) could be developed as efficient drug candidates.
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