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Computationally approached inhibition potential of Tinospora cordifolia towards COVID-19 targets.

ABSTRACT: The recent emergence of novel coronavirus (SARS-CoV-2) has been a major threat to human society, as the challenge of finding suitable drug or vaccine is not met till date. With increasing morbidity and mortality, the need for novel drug candidates is under great demand. The investigations are progressing towards COVID-19 therapeutics. Among the various strategies employed, the use of repurposed drugs is competing along with novel drug inventions. Based on the therapeutic significance, the chemical constituents from the extract of Tinospora cordifolia belonging to various classes like alkaloids, lignans, steroids and terpenoids are investigated as potential drug candidates for COVID-19. The inhibition potential of the proposed compounds against viral spike protein and human receptor ACE2 were evaluated by computational molecular modeling (Auto dock), along with their ADME/T properties. Prior to docking, the initial geometry of the compounds were optimized by Density functional theory (DFT) method employing B3LYP hybrid functional and 6-311 + + G (d,p) basis set. The results of molecular docking and ADME/T studies have revealed 6 constituents as potential drug candidates that can inhibit the binding of SARS-CoV-2 spike protein with the human receptor ACE2 protein. The narrowed down list of constituents from Tinospora cordifolia paved way for further tuning their ability to inhibit COVID-19 by modifying the chemical structures and by employing computational geometry optimization and docking methods.

Supplementary information

The online version contains supplementary material available at 10.1007/s13337-021-00666-7.

SUBMITTER: Jena S

PROVIDER: S-EPMC7980128 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Traditionally, Tinospora cordifolia is commonly used in the treatment of diabetes and obesity; has been evaluated for their anti-diabetic and anti-obese potency in experimental animal models. However, the binding affinity of multiple bioactives with various proteins involved in the pathogenesis of diabetes and obesity has not been reported yet. Hence, the present study aimed to assess the binding affinity of multiple bioactives from T. cordifolia with various targets involved in the pathogenesis of diabetes and obesity. The ligands and targets were retrieved from the PubChem and Protein Data Bank respectively and docked using autodock4.0. Druglikeness and absorption, distribution, metabolism, excretion, and toxicity profile were predicted using Molsoft and admetSAR1 respectively. The multiple bioactives from T. cordifolia were identified to interact with multiple proteins involved in the pathogenesis of diabetes/obesity, i.e., isocolumbin (- 9 kcal/mol) with adiponectin (PDB: 4DOU), β-sitosterol (- 10.9 kcal/mol) with cholesteryl ester transfer protein (PDB: 2OBD), tinocordiside (- 6.9 kcal/mol) with lamin A/C (PDB: 3GEF), berberine (- 9.5 kcal/mol) with JNK1 (PDB:3ELJ), β-sitosterol & isocolumbin (- 10.1 kcal/mol) with peroxisome proliferator-activated receptor-γ (PDB:4CI5), berberine (- 7.5 kcal/mol) with suppressor of cytokine signaling 3 (PDB: 2BBU), isocolumbin (- 9.6 kcal/mol) with pancreatic α-amylase (PDB: 1B2Y), isocolumbin (- 9 kcal/mol) with α-glucosidase (PDB: 3TOP), and β-sitosterol (- 10.8 kcal/mol) with aldose reductase (PDB: 3RX2). Similarly, among the selected bioactives, tembetarine scored highest druglikeness score, i.e., 1.21. In contrast, isocolumbin scored lowest drug-likeness character i.e. - 0.52. The predicted result of phytochemicals from T. cordifolia for acute oral toxicity, rat acute toxicity, fish toxicity, drug-likeness score, and aqueous solubility showed the probability of lower side/adverse effects in human consumption. The study suggests processing for bioactives from T. cordifolia against diabetes and obesity via in-vitro and in-vivo approaches.

Project description:BACKGROUND:Glutamate, the major excitatory neurotransmitter of CNS acts as a neurotoxin at higher concentrations. Prolonged activation of glutamate receptors results in progressive neuronal damage by aggravating calcium influx, inducing mitochondrial damage and oxidative stress. Excitotoxic cell death is associated with the pathogenesis of various neurodegenerative disorders such as trauma, brain injury and neurodegenerative diseases. The current study was designed to investigate the neuroprotective and neuroregenerative potential of Tinospora cordifolia against glutamate-induced excitotoxicity using primary cerebellar neuronal cultures as a model system. METHODS:Monosodium salt of glutamate was used to induce neurotoxic injury in primary cerebellar neurons. Four extracts including Hexane extract, Chloroform extract, Ethyl acetate, and Butanol extract were obtained from fractionation of previously reported aqueous ethanolic extract of T. cordifolia and tested for neuroprotective activity. Out of the four fractions, Butanol extract of T. cordifolia (B-TCE) exhibited neuroprotective potential by preventing degeneration of neurons induced by glutamate. Expression of different neuronal, apoptotic, inflammatory, cell cycle regulatory and plasticity markers was studied by immunostaining and Western blotting. Neurite outgrowth and migration were also studied using primary explant cultures, wound scratch and gelatin zymogram assay. RESULTS:At molecular level, B-TCE pretreatment of glutamate-treated cultures normalized the stress-induced downregulation in the expression of neuronal markers (MAP-2, GAP-43, NF200) and anti-apoptotic marker (Bcl-xL). Further, cells exposed to glutamate showed enhanced expression of inflammatory (NF-?B, AP-1) and senescence markers (HSP70, Mortalin) as well as the extent of mitochondrial damage. However, B-TCE pretreatment prevented this increase and inhibited glutamate-induced onset of inflammation, stress and mitochondrial membrane damage. Furthermore, B-TCE was observed to promote regeneration, migration and plasticity of cerebellar neurons, which was otherwise significantly inhibited by glutamate treatment. CONCLUSION:These results suggest that B-TCE may have neuroprotective and neuroregenerative potential against catastrophic consequences of glutamate-mediated excitotoxicity and could be a potential therapeutic candidate for neurodegenerative diseases.

Project description:BackgroundSARS-CoV-2 infections caused mild-to-moderate illness. However, a sizable portion of infected people experience a rapid progression of hyper-inflammatory and hypoxic respiratory illness that necessitates an effective and safer remedy to combat COVID-19.MethodsA total of 150 COVID-19-positive patients with no to mild symptoms, between the age groups 19-65 years were enrolled in this randomized, open-labeled three-armed clinical trial. Among them, 136 patients completed the study with RT-PCR negative reports. The patients received herbal drugs orally (Group A (Adhatoda vasica; AV; 500 mg; n = 50); Group B (Tinospora cordifolia; TC; 500 mg; n = 43), and Group C (AV + TC; 250 mg each; n = 43)) for 14 days. Clinical symptoms, vital parameters, and viral clearance were taken as primary outcomes, and biochemical, hematological parameters, cytokines, and biomarkers were evaluated at three time points as secondary outcomes.ResultsWe found that the mean viral clearance time was 13.92 days (95% confidence interval [CI] 12.85-14.99) in Group A, 13.44 days (95% confidence interval [CI] 12.14-14.74) in Group B, and 11.86 days (95% confidence interval [CI] 10.62-13.11) days in Group C. Over a period of 14 days, the mean temperature in Groups A, and B significantly decreased linearly. In Group A, during the trial period, eosinophils, and PT/INR increased significantly, while monocytes, SGOT, globulin, serum ferritin, and HIF-1α, a marker of hypoxia reduced significantly. On the other hand, in Group B hsCRP decreased at mid-treatment. Eosinophil levels increased in Group C during the treatment, while MCP-3 levels were significantly reduced.ConclusionsAll the patients of the three-armed interventions recovered from COVID-19 and none of them reported any adverse effects from the drugs. Group C patients (AV + TC) resulted in a quicker viral clearance as compared to the other two groups. We provide the first clinical report of AV herbal extract acting as a modifier of HIF-1α in COVID-19 patients along with a reduction in levels of ferritin, VEGF, and PT/INR as the markers of hypoxia, inflammation, and thrombosis highlighting the potential use in progression stages, whereas the TC group showed immunomodulatory effects. Trial registration Clinical Trials Database -India (ICMR-NIMS), CTRI/2020/09/028043. Registered 24th September 2020, https://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=47443&EncHid=&modid=&compid=%27,%2747443det%27.

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Computationally approached inhibition potential of Tinospora cordifolia towards COVID-19 targets.

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