The pandemic caused by novel coronavirus disease 2019 infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (M pro ) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of M pro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of M pro . However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure-and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies. ARTICLE HISTORY

Chickpea plants were subjected to salt stress for 48 h with 100 mM NaCl, after 50 days of growth. Other batches of plants were simultaneously treated with 0.2 mM sodium nitroprusside (NO donor) or 0.5 mM putrescine (polyamine) to examine their antioxidant effects. Sodium chloride stress adversely affected the relative water content (RWC), electrolyte leakage and lipid peroxidation in leaves. Sodium nitroprusside and putrescine could completely ameliorate the toxic effects of salt stress on electrolyte leakage and lipid peroxidation and partially on RWC. No significant decline in chlorophyll content under salt stress as well as with other treatments was observed. Sodium chloride stress activated the antioxidant defense system by increasing the activities of peroxidase (POX), catalase (CAT) superoxide dismutase (SOD) and ascorbate peroxidase (APX). However no significant effect was observed on glutathione reductase (GR) and dehydro ascorbate reductase (DHAR) activities. Both putrescine and NO had a positive effect on antioxidant enzymes under salt stress. Putrescine was more effective in scavenging superoxide radical as it increased the SOD activity under salt stress whereas nitric oxide was effective in hydrolyzing H 2 O 2 by increasing the activities of CAT, POX and APX under salt stress.

The dynamics and plasticity of the PD-1/PD-L1 axis are the bottlenecks for the discovery of small-molecule antagonists to perturb this interaction interface significantly. Understanding the process of this protein−protein interaction (PPI) is of fundamental biological interest in structure-based drug designing. Food and Drug Administration (FDA)-approved anti-PD-1 monoclonal antibodies (mAbs) are the first-in-class with distinct binding modes to access this axis clinically; however, their mechanistic aspects remain elusive. Here, we have unveiled the interactive interfaces with PD-L1 and mAbs to investigate the native plasticity of PD-1 at global (structural and dynamical) and local (residue side-chain orientations) levels. We found that the structural stability and coordinated C α movements are increased in the presence of PD-1's binding partners. The rigorous analysis of these PPIs using computational biophysical approaches revealed PD-1ʼs intrinsic plasticity, its concerted loops' movement (BC, FG, and CC′), distal side-chain motions, and the thermodynamic landscape, which are perturbed remarkably from its unbound to bound states. Based on intra-/inter-residues' contact networks and energetics, the hot-spots have been identified that were found to be essential to arrest the dynamical motions of PD-1 significantly for the rational design of therapeutic agents by mimicking the mAbs mechanism.

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Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (M Pro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.

Perturbation in lipid homeostasis is one of the major bottlenecks in metabolic diseases, especially Non-alcoholic Fatty Liver Disease (NAFLD), which has emerged as a leading global cause of chronic liver disease. The bile acids (BAs) and their derivatives exert a variety of metabolic effects through complex and intertwined pathways, thus becoming the attractive target for metabolic syndrome treatment. To modulate the lipid homeostasis, the role of BAs, turn out to be paramount as it is essential for the absorption, transport of dietary lipids, regulation of metabolic enzymes and transporters that are essential for lipid modulation, flux, and excretion. The synthesis and transport of BAs (conjugated and unconjugated) is chiefly controlled by nuclear receptors and the uptake of long-chain fatty acids (LCFA) and BA conjugation via transporters. Among them, from in-vivo studies, farnesoid X receptor (FXR) and liver-specific fatty acid transport protein 5 (FATP5) have shown convincing evidence for their key roles in lipid homeostasis and reversal of fatty liver disease substantially. BAs have a wider range of biological effects as they are identified as modulators for FXR and FATP5 both and therefore hold a significant promise for altering the lipid content in the treatment of a metabolic disorder. BAs also have received noteworthy interest in drug delivery research due to its peculiar physicochemical properties and biocompatibility. Here, we are highlighting the connecting possibility of BAs as an agonist for FXR and antagonist for FATP5, paving an avenue to target them for designing synthetic small molecules for lipid homeostasis.

Finger millet, an orphan crop, possesses immense potential in mitigating climate change and could offer threefold security in terms of food, fodder, and nutrition. It is mostly cultivated as a subsistence crop in the marginal areas of plains and hills. Considering the changes in climate inclusive of recurrent weather vagaries witnessed every year, it is crucial to select stable, high-yielding, area-specific, finger millet cultivars. Sixty finger millet varieties released across the country were evaluated over six consecutive rainy seasons from 2011 to 2016 at the Agricultural Research Station, Vizianagaram. The genotype × environment interaction (GEI) was found to be significant in the combined ANOVA. Furthermore, the Additive Main effects and Multiplicative Interaction (AMMI) analysis asserted that genotypes and the GEI effects accounted for approximately 89% of the total variation. Strong positive associations were observed in an estimated set of eleven stability parameters which were chosen to identify stable genotypes. Furthermore, Non-parametric and Parametric Simultaneous Selection indices (NP-SSI and P-SSI) were calculated utilizing AMMI-based stability parameter (ASTAB), modified AMMI stability value (MASV), and Modified AMMI Stability Index (MASI) to identify stable high yielders. Both methods had inherent difficulties in ranking genotypes for SSI. To overcome this, the initial culling [i.e., SSI with culling strategy (C-SSI)] of genotypes was introduced for stability. In the C-SSI method, the top ten genotypes were above-average yielders, while those with below-average yield were observed in NP-SSI and P-SSI methods. Similarly, the estimation of best linear unbiased prediction (BLUP)-based simultaneous selections, such as harmonic mean of genotypic values (HMGV), relative performance of genotypic values (RPGV), and harmonic mean of relative performance of genotypic values (HMRPGV), revealed that none of the top ten entries had below-average yield. The study has proven that C-SSI and BLUP-based methods were equally worthy in the selection of high-yielding genotypes with stable performance. However, the C-SSI approach could be the best method to ensure that genotypes with a considerable amount of stability are selected. The multi-year trial SSI revealed that entries Indaf-9, Sri Chaitanya, PR-202, and A-404; and VL324 and VL146 were ascertained to be the most stable high-yielding genotypes among medium-to-late and early maturity groups, respectively.

The present study investigates the effect of long and short term Cd stress in chickpea plants and evaluates the protective effect of exogenous nitric oxide (NO) supplementation using sodium nitroprusside (SNP). Cadmium treatments were given before sowing (long term stress) and thirty days after germination (short term stress). Sodium nitroprusside was given as foliar spray 30 days after germination to both long and short term Cd treated plants. Cadmium adversely affected the membranes as was evident from increased electrolyte leakage and lipid peroxidation levels. Sodium nitroprusside treatments decreased ion leakage and lipid peroxidation levels significantly. Short term Cd stress resulted in a higher induction of the catalase, peroxidase, ascorbate peroxidase, glutathione reductase and superoxide dismutase as compared to long term Cd stress. Nitric oxide showed its positive effect by further increasing the activities of antioxidant enzymes. Cadmium stress also altered the level of antioxidant metabolites by reducing the ascorbate redox ratio (ASC/DHA) and glutathione redox ratio (GSH/GSSG). Sodium nitroprusside treatments increased the redox ratios. Cadmium also adversely affected the seed yield and a greater decline was observed with long term Cd stress as compared to short term Cd stress. Nitric oxide had a positive effect on seed yield and Cd accumulation. The study concludes that an exogenous supply of NO protects chickpea plants from Cd toxicity.