10 research outputs found
3D-QSAR, molecular dynamics simulations, and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors
No full textKYASANUR FOREST DISEASE: A REGIONAL REPORT OF EPIDEMIOLOGY, PATHOGENESIS AND ITS CLINICAL MANIFESTATIONS
No full textKyasanur Forest Disease (KFD), also known as Kyasanur Forest Virus (KFDV) infection, is a virus that mostly affects humans and monkeys. It was first discovered in the Kyasanur Forest in Karnataka, India, in 1957, hence its name is Kyasanur Forest Disease. The Kyasanur Forest Disease virus, a member of the Flaviviridae family and a close relative of the tick-borne encephalitis virus, is the culprit behind KFD. The Haemaphysalis spinigera tick species, which act as the virus\u27s reservoir and vector, is particularly known for carrying the disease through its bite. The primary hosts of KFDV are thought to be monkeys, which also serve as amplification hosts and help the virus propagate among tick populations. Signs and symptoms of KFD are similar to those of other viral illnesses, such as a high fever, headache, muscle soreness, and exhaustion. Some people may experience more serious symptoms, such as hemorrhagic signs and neurological issues which further resulted in death. KFD management mostly involves supportive care to manage symptoms and avoid complications because there is no particular antiviral medication for the disease. The Kyasanur Forest Disease is primarily seen in southern India and is regarded as an emerging infectious disease with a small geographic spread. However, occasional cases and outbreaks have also been documented in nearby areas. In order to provide more efficient prevention measures and therapies for KFD, the present regional report strives to better understand the epidemiology, pathophysiology, and potential risk factors connected with this condition.The article also discusses future perspectives and strategies to address Kyasanur Forest Disease (KFD), providing valuable insights that could guide the development of more effective treatments and preventive measures in the future
IN-SILICO PREDICTION OF THE NEUROINFLAMMATION MECHANISM OF CAPPARIS SEPIARIA
No full textNeuroinflammation or neural dysfunction is a major risk factor that can initiate multiple intracellular signaling cascades to release different proinflammatory cytokines, chemokines and various reactive oxygen species leading to multiple neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. The adverse effects associated with the long-term use of conventional non-steroidal anti-inflammatory drugs is attracting herbal medicines as potential therapeutic candidates worldwide. Capparis sepiaria L (C. sepiaria) belonging to Capparaeae is therapeutic medicinal plant used to relieve various ailments including skin diseases, tumours, blood purification, toxaemia, snakebite and disease of the muscles. The objective of this study is to determine the pharmacokinetic and pharmacodynamic properties of C.sepiaria phyto-constituents as therapeutic molecules against neuro inflammation by using in-silico docking analysis and drug disposition. Six phyto- constituents identified from the leaves of C. sepiaria were docked against six pro-inflammatory markers of neuroinflammation followed by the prediction of their safety and bioavailability using GOLD 5.2, admetSAR softwareS respectively. The docking scores obtained were comparable and even better than the five standard marketed drugs. β-amyrin and quercetine present in the leaves of C.sepiaria showed highest fitness score with P38 MAP kinase, NF-kB, mTOR, TACE AChE, BChE markers which are also the targets of the drugs like Galantamine, Donepazil and Rivastigmine. To our understanding this is the first study investgating the inhibitory effect of C. sepiaria in the neuroinflammation. Thus, Capparis sepiaria may prove to be a potential antineuroinflammatory agent and may be further explored as a potential therapeutic candidate for the management of neurodegenerative diseases.
 
Unravelling the neuroprotective effects of taxifolin against scopolamine-induced dementia in male Sprague Dawley rats: A comprehensive preclinical investigation
No full textBackground/objective: Alzheimer's disease is a neurodegenerative disorder which impacts millions of individuals worldwide, is driven by cholinergic neuron degeneration. The current research examined taxifolin's neuroprotective effects against scopolamine-induced dementia in rats. Methods: Twenty male Sprague-Dawley rats were assigned into four groups (5 rats/group). Group I (control group) and Group II (disease group) received saline intraperitoneally for five days. Group III (treatment group) received taxifolin (5 mg/kg, i.p.) for five days. Group IV (positive control) received donepezil (2 mg/kg, i.p.) for five days. Except Group I all the other Groups received scopolamine (2 mg/kg, i.p.) on day five. Cognitive abilities were evaluated using the Y-maze, Morris water maze, and Cook's pole climbing tests. Post-euthanasia, brain samples were analysed for acetylcholinesterase activity, oxidative stress markers (lipid peroxidation, nitrite levels), antioxidant enzymes (superoxide dismutase, catalase, reduced glutathione), and inflammation (myeloperoxidase activity). Molecular docking was performed to evaluate taxifolin's binding with acetylcholinesterase. In silico studies were done to analyse pharmacokinetic and toxicological properties of taxifolin. Results: Scopolamine caused memory impairment, altered the brain's histopathology, increased acetylcholinesterase activity, lipid peroxidation, nitrite levels, and myeloperoxidase activity, while altering antioxidant enzymes. Taxifolin pre-treatment reversed these alterations, improving cognitive function, reducing oxidative stress and inflammation, and restoring antioxidant enzymes. Molecular docking showed taxifolin inhibited acetylcholinesterase with a docking score of 55, while in silico studies revealed favourable pharmacokinetic and toxicological profiles. Conclusion: Taxifolin effectively mitigates scopolamine-induced cognitive and biochemical impairments, suggesting its potential as a therapeutic candidate for Alzheimer's disease. Further studies are required to validate these findings
Dielectric and electrical properties of binary mixtures of 1-butyl-3-methylimadazolium and water in the frequency range 20 Hz to 2 MHz
No full textTHE ROLE OF HERBAL COSMETICS FOR THE MITIGATION OF THE PSORIASIS
No full textPsoriasis is a chronic inflammatory skin disease with a strong genetic predisposition and autoimmune pathogenicity. The potential molecular targets for psoriasis are JAK, STAT3, Interleukin 8. By inhibiting theses targets it marks in alteration in immune response and suppresses the abnormal activation of inflammatory cascade like psoriasis. The lack of possible cure and certain adverse reactions to several synthetic treatments has led toextensive research for anti-psoriatic activity in herbal based formulation. The recent synthetic treatments available for treating psoriasis include phototherapy, oral medications like methotrexate, cyclosporine, and azathioprine but due to severe side effects of phototherapy which include pain, uneven pigmentation and scarring and certain side effects of oral medications like methotrexate increased the risk of liver fibrosis, cyclosporine can lead to hypertriglyceridemia. Due to these severe side effects which can lead to discomfort in the body. Therefore, the herbal preparations which are naturally available can avoid this problem and can be used to treat psoriasis. This review aimed for the exploration of the herbal cream formulation containing pure herbs, viz. oil extracts and methanolic extracts, extract of leaves of basil, thyme tulsi, turmeric, neem, beeswax, olive oil, rose oil assessed the antipsoriatic activity of various cream formulation
Discovery of novel CaMK-II inhibitor for the possible mitigation of arrhythmia through pharmacophore modelling, virtual screening, molecular docking, and toxicity prediction
No full textIn the present research, a few well-known artificial intelligence tools were explored for efficient hit selection which could be further utilized for the discovery of CaMK-II inhibitors for the Treatment of arrhythmia. To achieve the desired goals pharmacophore modelling, database retrieval, molecular docking studies, and toxicity prediction were performed. Pharmacophore modelling was performed with the Pharmit open-source database which gave the features viz. Hydrogen Bond Donor, Hydrogen Bond Acceptor, and Hydrophobic. This pharmacophore is generated with the aid of the protein of CaMK-II (PDB ID: 2WEL) and co-crystallized ligand K88. Further, this generated pharmacophore was screened through the various Pharmit databases which include CHEMBL30, ChemDiv, ChemSpace, MCULE, MolPort, NCI Open Chemical Repository, Lab Network, and ZINC. Further, the top two hits from each database that has maximum similarity with the pharmacophore have been selected for the molecular docking and ADMET studies. Among, all the hits CHEMBL 1952032 showed good binding interactions with CaMK-II. Also, it was found to be non-toxic upon evaluation through the OSIRIS property explorer. In the future, it can be explored against the CaMK-II for the development of novel CaMK-II inhibitors which can be used for the mitigation of arrhythmia
Tetrahydroquinoline: an efficient scaffold as mTOR inhibitor for the treatment of lung cancer - Supplementary Information.docx
No full text
Figure SF 01
Lung cancer and its classification
Figure SF 02
Structure of mTOR backbone, which consists of six region the HEAT, FAT (domain focal adhesion targeting domain), FRB (FKBP12 rapamycin binding), KIN (kinase, the target of ATP competitive inhibitors), NRD, and FATC (focal adhesion targeting domain of C-terminal). & Structures of mTORC1 (mTOR complex)1/2. mTORC1 which contains of the mTOR backbone, Raptor, Deptor, mLST8, PRAS40, and mTORC2, which contains of mTOR backbone, Protor, Rictor, Deptor, mSlN1, and mLST8.
Figure SF 03
Structure of some “nib” group of molecules like some EGFR inhibitors viz. 29. Erlotinib & 30. Gifitinib, a tyrosine kinase inhibitor 31. Neratinib, a MEK kinase inhibitor 32. Selumetinib, 33. Cobimetinib/GDC-0973, an ERK inhibitor 34. Trametinib all are used to treat lung cancers.
Figure SF 04
Timeline indicates tetrahydroquinoline derivatives either as a mTOR inhibitor or for the treatment of lung cancer in last ten years.
Table ST 01
Some known mTOR inhibitors
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Morpholine-Substituted Tetrahydroquinoline Derivatives as Potential mTOR Inhibitors: Synthesis, Computational Insights, and Cellular Analysis
No full textBackgrounds: This study explores the design of substituted tetrahydroquinoline (THQ) derivatives and their synthesis as possible inhibitors of mTOR inhibitors for targeted cancer therapy. Methods: Inspired by the structural characteristics of known mTOR inhibitors, eight novel derivatives were synthesized, characterized using mass spectroscopy, 1H, and 13C NMR, and evaluated for anticancer activity. Results: Computational studies, including molecular docking and molecular dynamics (MD) simulations, highlighted the derivative’s strong binding interaction and stability within the mTOR active site. Assays for in vitro cytotoxicity showed strong and specific anticancer action against cell lines of triple-negative breast cancer, lung cancer, and breast cancer while causing negligible impact on healthy cells. Conclusions: Compound 10e emerged as the most promising candidate, displaying exceptional activity against A549 cells (IC50 = 0.033 µM) and inducing apoptosis in a dose-dependent manner, surpassing standard agents, like Everolimus and 5-flurouracil. Structure–activity relationship analysis revealed that incorporating trifluoromethyl and morpholine moieties significantly enhanced selectivity and potency. MD simulations further validated these findings, confirming stable protein-ligand interactions and favorable dynamics over a 100-ns simulation period. Collectively, this study underscores the therapeutic potential of THQ derivatives, particularly compound 10e, as promising mTOR inhibitors with potential applications in lung cancer treatment
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Rainfall trends in India and their impact on soil erosion and land management
No full textUnder the threat of global warming it is vital to determine the impact that future changes in climate may have on the environment and to what extent any adverse effects can be mitigated. In this research an assessment was carried out on the impact that climate trends may have on soil erosion and contaminant transport in India and examined the potential for top soil management practices to improve or maintain soil quality. Historical rainfall data from 50-135 years and extreme temperature data for 103 years were analysed and long term trends were assessed for various aspects of Indian climates using suitable statistical techniques. Results indicated that intra-region variability for extreme monsoon seasonal rainfall is large and mostly exhibited a negative tendency leading to increasing frequency and magnitude of monsoon rainfall deficit and decreasing frequency and magnitude of monsoon rainfall excess everywhere in India except in the peninsular Indian region. This is further exacerbated by increased and more variable extreme temperatures. Intra-region rainfall variability in India is linked to the pacific Southern Oscillation, where the associations of monsoon drought and El-Niño Southern Oscillation (ENSO) in the regions near to coast are greatest. 50-years high resolution daily gridded rainfall data was analysed to set up certain indices for the extreme daily rainfalls to assess their changes for the six gridded regions of Kerala, the extreme south western state of India where monsoon rainfall initiates every year. This was also done for two study sites, namely Bhoj wetland area of west central India and Sukinda chromite mining site of central north east India. Significant decrease was found in monsoon and spring rainfall extremes and increase in winter and autumn rainfall extremes in Kerala that would affect the tendency of change in seasonal total rainfall as well. Decrease in monsoon rainfall in Kerala also indicate that monsoon rainfall is decreasing in India as a whole, increased occurrence of floods is expected in winter and autumn seasons, together with water scarcity are expected to be felt both in spring and monsoon seasons with a delaying monsoon onset in Kerala. Soil erosion studies were conducted for two northern most gridded regions of Kerala as an extended work of the related MPhil study, and contaminant transport with eroded sediments was looked at for the Bhoj and Sukinda sites using RUSLE2 model software and other suitable numerical methods. It was found that soil erosion depended on a complex interaction of climate, soil properties, topography, and cover management. An assessment on extreme climate patterns for Bhoj and Sukinda showed an increasing tendency of seasonal and annual rainfall extremes and temperatures leading to an increasing pattern of soil erosion at both the sites. However, a certain consensus was difficult to reach because of the complex interaction of climate and soil carbon that is a very important deciding factor for soil erosion potential. Vegetative cover and plant residue was found providing essential soil nutrients, enhancing soil properties and retarding rainfall impact on bare top soil leading to reduction of soil erosion. Therefore, a soil erosion and contaminant transport prevention plan should take care of the top soil such that it is not kept bare especially when rainfall intensity is high in a given year. This work as a whole has highlighted the importance of regional climatological analysis with the large scale spatial averages especially at local decision making level, which is very useful for the broad scenarios such as climatological and ecological risk management
