The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.
The effects of a urease inhibitor [N-(n-butyl) thiophosphoric triamide (nBTPT-trade name Agrotain®)] alone and a combination of nitrification inhibitor dicyandiamide (DCD) and nBTPT, defined as a double inhibitor (DI), on urea fertilizer use efficiency in pastoral systems were investigated. The treatments comprised urea alone, urea with nBTPT, urea with DI at a low rate (LDI), and urea with DI at a high rate (HDI). Each treatment had three replicates and was applied at two rates-30 and 60 kg nitrogen (N) ha-1 to three trial sites (North Island-1, North Island-2 and South Island) in New Zealand during the 2005-2006 seasons. The trials at North Island-1 and South Island received six applications of fertilizers, giving total N application rates of 180 and 360 kg N ha-1 over an18-month period. The North Island-2 trial received these treatments five times during a one-year period, giving total N application rates of 150 and 300 kg N ha-1. Soil samples collected after the first fertilizer application from the South Island trial indicated that compared to urea alone, urea with nBTPT and urea with the DI treatments applied at the 60 kg N ha-1 rate exhibited a significantly slower release of ammonium-N during the first two weeks. Nitrate-N production was only partially delayed by DCD applied in the DI treatment during the first week. On individual site and over all sites, urea applied with nBTPT and, to a lesser extent, urea applied with the DI treatment consistently produced significantly higher pasture dry matter (PDM) and nitrogen response efficiency (NRE), relative to pastures receiving urea alone at the two N rates. Across all three sites at the 30 kg N ha-1 rate, over the entire period, urea with nBTPT produced 20,441 kg DM ha-1 compared to 18,383 kg DM ha-1 produced by urea alone, representing an increase of 11.2% over urea alone. At the 60 kg N ha-1 rate, the increase in PDM by urea with nBTPT was 8.3% over urea alone. PDM yields from urea with LDI and HDI treatments were slightly lower than PDM yields of pastures receiving urea with nBTPT, but significantly higher than those of urea alone. The NRE of individual sites and over all sites were significantly higher for the treatments of urea + nBTPT, or urea + DI, relative to those pastures receiving urea alone. NRE values dropped at the higher urea rate (60 kg N ha-1). Compared to urea alone, urea with nBTPT or urea with the DI treatments also showed an improvement in N uptake in pasture herbage. However, these improvements in pasture N uptake were only significant for HDI and LDI treatments at 60 kg N ha-1. This suggests that applying urea with nBTPT alone has the most potential to improve the efficiency of urea fertilizer use. The DI treatments may have other environmental benefits, like reduction in N 2 O emission and NO 3 leaching, though the agronomic benefits appear unlikely to be greater than those achieved by using urea with nBTPT alone.
The recent coronavirus outbreak has changed the world’s economy and health sectors due to the high mortality and transmission rates. Because the development of new effective vaccines or treatments against the virus can take time, an urgent need exists for the rapid development and design of new drug candidates to combat this pathogen. Here, we obtained antiviral peptides obtained from the data repository of antimicrobial peptides (DRAMP) and screened their predicted tertiary structures for the ability to inhibit the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using multiple combinatorial docking programs, including PatchDock, FireDock, and ClusPro. The four best peptides, DRAMP00877, DRAMP02333, DRAMP02669, and DRAMP03804, had binding energies of −1125.3, −1084.5, −1005.2, and −924.2 Kcal/mol, respectively, as determined using ClusPro, and binding energies of −55.37, −50.96, −49.25, −54.81 Kcal/mol, respectively, as determined using FireDock, which were better binding energy values than observed for other peptide molecules. These peptides were found to bind with the active cavity of the SARS-CoV-2 main protease; at Glu166, Cys145, Asn142, Phe140, and Met165, in addition to the substrate-binding sites, Domain 2 and Domain 3, whereas fewer interactions were observed with Domain 1. The docking studies were further confirmed by a molecular dynamics simulation study, in which several descriptors, including the root-mean-square difference (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), and hydrogen bond formation, confirmed the stable nature of the peptide–main protease complexes. Toxicity and allergenicity studies confirmed the non-allergenic nature of the peptides. This present study suggests that these identified antiviral peptide molecules might inhibit the main protease of SARS-CoV-2, although further wet-lab experiments remain necessary to verify these findings.
Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of −8.4, −8.5, and −8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein–compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.
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