In-silico study of some natural plant phyto-compounds for the identification of novel potent cholinesterase inhibitors against Alzheimer's Disease

The main aim of this study is to identify inhibitory binding potent of the available commercially alkaloids, against the crystal structure of acetylcholinesterase (AChE) protein by in silico studies. The inhibitory data of the compounds should be compared with the internal ligand as well as standard AChE inhibitor Aricept (which is used for the treatment of all stages of Alzheimer’s disease). AutoDock 4.0 is used for the docking study, conformational orientation site analysis, and, with the help of docking, we have calculated parameters like binding energy and inhibition constant. Docking's study showed that Glabridin, Isorosmanol, Quercetin, Honokiol, Eckol, Sargaquinoic acid, and Ginsedosides revealed strong binding affinity with the enzyme. Moreover, The ADMET profiling and physicochemical properties of the selected compounds are evaluated using the Molinspiration and Data warrior software. By showing a strong binding affinity value, positive bioactivity score, and good pharmacokinetic properties, the top compound was determined. After evaluation with all parameters, the compound Glabridin and Ginsedosides show the most potent inhibitory effect towards the acetylcholinesterase, so this compound could be used as a novel is required to treat Alzheimer's disease.

Anti-Methanogenic Effect of Phytochemicals on Methyl-Coenzyme M Reductase—Potential: In Silico and Molecular Docking Studies for Environmental Protection

Methane is a greenhouse gas which poses a great threat to life on earth as its emissions directly contribute to global warming and methane has a 28-fold higher warming potential over that of carbon dioxide. Ruminants have been identified as a major source of methane emission as a result of methanogenesis by their respective gut microbiomes. Various plants produce highly bioactive compounds which can be investigated to find a potential inhibitor of methyl-coenzyme M reductase (the target protein for methanogenesis). To speed up the process and to limit the use of laboratory resources, the present study uses an in-silico molecular docking approach to explore the anti-methanogenic properties of phytochemicals from Cymbopogon citratus, Origanum vulgare, Lavandula officinalis, Cinnamomum zeylanicum, Piper betle, Cuminum cyminum, Ocimum gratissimum, Salvia sclarea, Allium sativum, Rosmarinus officinalis and Thymus vulgaris. A total of 168 compounds from 11 plants were virtually screened. Finally, 25 scrutinized compounds were evaluated against methyl-coenzyme M reductase (MCR) protein using the AutoDock 4.0 program. In conclusion, the study identified 21 out of 25 compounds against inhibition of the MCR protein. Particularly, five compounds: rosmarinic acid (−10.71 kcal/mol), biotin (−9.38 kcal/mol), α-cadinol (−8.16 kcal/mol), (3R,3aS,6R,6aR)-3-(2H-1,3-benzodioxol-4-yl)-6-(2H-1,3-benzodioxol-5-yl)-hexahydrofuro[3,4-c]furan-1-one (−12.21 kcal/mol), and 2,4,7,9-tetramethyl-5decyn4,7diol (−9.02 kcal/mol) showed higher binding energy towards the MCR protein. In turn, these compounds have potential utility as rumen methanogenic inhibitors in the proposed methane inhibitor program. Ultimately, molecular dynamics simulations of rosmarinic acid and (3R,3aS,6R,6aR) -3-(2H-1,3-benzodioxol-4-yl)-6-(2H-1,3-benzodioxol-5-yl)-hexahydrofuro[3,4-c]furan-1-one yielded the best possible interaction and stability with the active site of 5A8K protein for 20 ns.

Screening assessment of trimethoxy flavonoid and - (-)-epigallocatechin-3-gallate against formalin-induced arthritis in Swiss albino rats and binding properties on NF-κB-MMP9 proteins

Background The isolated trimethoxy flavonoid 4a,5,8,8a-tetrahydro-5-hydroxy-3,7,8-trimethoxy-2-(3,4-dimethoxyphenyl) chromen-4-one (TMF) from methanolic stem extract of T chrysantha (METC) and - (-)-epigallocatechin-3-gallate (EGCG) can be used to suppress acute inflammation and arthritis as an ethical medicine in Ayurveda. The nuclear factor kappa beta (NF-κB) signaling is involved in the expression of inflammatory mediators such as TNF-α and IL-1β. A successive investigation of NF-κB–MMP9 signaling during the production of inflammatory mediators needs to be developed. The docking studies of compounds TMF and EGCG were carried out using Autodock 4.0 and Discovery studio Biovia 2017 software to find out the interaction between ligand and the target proteins. The anti-arthritic potential of TMF, EGCG, and indomethacin was evaluated against formalin-induced arthritis in Swiss albino rats. Arthritis was assessed by checking the mean increase in paw diameter for 6 days via digital vernier caliper. The blood cell counter and diagnostic kits measured the different blood parameters and Rheumatoid factor (RF, IU/mL). The interleukin-1β (IL-1β) and tumor necrosis factor (TNFα) in serum were determined by ELISA, and the pERK, MMP9, and NF-κB expressions in the inflamed tissue were determined by Western blotting, respectively. The mRNA expression for inflammatory marker enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was determined by qRT-PCR. Results Based on grid score, interactions, and IC50 values in molecular docking studies, the TMF and EGCG can be effectively combined with proteins NF-kB and MMP9. The TMF-HD and EGCG-HD better suppressed the acute inflammation and arthritis with marked low-density pERK, MMP9, NF-κB, iNOS, COX-2 levels. The endogenous antioxidant levels were increased in TMF and EGCG treated rats. Conclusion The TMF and EGCG effectively unraveled acute inflammation and arthritis by suppressing NF-κB mediated MMP9 and cytokines. Graphic abstract

In-Silico Study of Some Natural Plant Phyto-compounds for the Identification of Novel Potent Cholinesterase Inhibitors Against Alzheimer Disease

The main aim of this study is to identify inhibitory binding potent of the available commercially alkaloids, against the crystal structure of acetylcholinesterase (AChE) protein by in silico studies. The inhibitory data of the compounds should be compared with the internal ligand as well as standard AChE inhibitor Aricept (which is used for the treatment of all stages of Alzheimer’s disease). AutoDock 4.0 is used for the docking study, conformational orientation site analysis, and, with the help of docking, we have calculated parameters like binding energy and inhibition constant. Docking's study showed that Glabridin, Isorosmanol, Quercetin, Honokiol, Eckol, Sargaquinoic acid, and Ginsedosides revealed strong binding affinity with the enzyme. Moreover, The ADMET profiling and physicochemical properties of the selected compounds are evaluated using the Molinspiration and Data warrior software. By showing a strong binding affinity value, positive bioactivity score, and good pharmacokinetic properties, the top compound was determined. After evaluation with all parameters, the compound Glabridin and Ginsedosides show the most potent inhibitory effect towards the acetylcholinesterase, so this compound could be used as a novel is required to treat Alzheimer's disease.

COVID-19: An In-Silico Analysis on Potential Therapeutic Uses of Trikadu as Immune System Boosters

Corona virus pandemic outbreak also known as COVID-19 has created an imbalance in this World. With the vaccines still in the trials, Scientists have adopted the use of natural or alternative medicines which are consumed mostly as dietary supplements to boost the immune system using herbal remedies. India is famous for traditional medicinal formulations which includes, ‘Trikadu’ –A combination of three acrids namely Zingiber officinale, Piper nigrum and Piper longum which has antioxidant properties that boost our immune system hence acting as a strong preventive measure. In this study AutoDock 4.0 was used to study interaction between the phytocompounds of Trikadu with RNA Dependant polymerase protein and Enveloped protein of the virus. Analysis of the results showed that Coumarin, Coumaperine and Bisdemethoxycurcumin showed strong bonding interactions with both the proteins. We can conclude that Trikadu are the potential molecules which can be incorporated in the diet to boost the immune system as a preventive measure against the virus.

GC-MS Analysis and Molecular Docking Studies of Active Phytochemicals from Medicinal Plants against Malassezia Globosa LIP1 (SMG1) Enzyme

Malassezia globosa LIP1 (SMG1) lipase plays a crucial role in the pathogenicity of M. globosa in dandruff sufferers. In this study, GC-MS analysis of selected medicinal plants was done, and antifungal activity of these identified phytochemicals was checked by molecular docking method against Malassezia globosa LIP1 (SMG1) lipase using AutoDock 4.0. SwissADME tool was used to analyze the absorption, distribution, metabolism, excretion (ADME) of phytoligands. GC-MS showed various phytoconstituents in the Glycyrrhiza glabra extract, including glabridin, 2-propenal, 3-phenyl-eugenol, 4'-O-methylglabridin, hispaglabridin A, stigmast-5-en-3-ol, stigmasta-5,3-dien-7-one, glabrol. Punica granatum extract contains hydroxymethylfurfural, stigmast-5-en-3-ol, 4h-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl-, 1,2,3-benzenetriol, d-glucopyranose, 1,6-anhydro- as the major compounds. Among one hundred thirty screened compounds, twenty-one followed Lipinski’s rule of five and were nontoxic in nature. Docking results reveal that among all, β-sitosterol, stigmatsa-5,3-dien- 7-one, glabrol and 22,23-dibromostigmast-5-en-3-yl acetate (DBSA) showed the highest binding affinity with SMG1 i.e. -6.29 kcal/mol, -6.50 kcal/mol, -10.12 kcal/mol and -11.04 kcal/mol respectively as compared to standard inhibitor RHC 80267 (-5.83 kcal/mol). From the results, we conclude that the lead compounds may be used as potential anti-dandruff agents. Plant-based anti-dandruff products are eco-friendly and considered a safe alternative due to their less or negligible side effects.

MOLECULAR DOCKING ANALYSES OF SOME CYCLOHEXADIENE DERIVATIVES

The molecular docking study was performed with aim to examine the inhibitory potency of two selected cyclohexadiene derivatives (cis-(1S)-3-Fluoro-3,5-cyclohexadiene-1,2-diol (1), and 1,1′-(3,5-Cyclohexadiene-1,3-diyl)dibenzene (2)). The inhibitory potency of compounds 1 and 2 was investigated toward Urokinase Type Plasminogen Activator (uPa). For this purpose AutoDock 4.0 software was used. The thermodynamic parameters achieved from molecular docking simulations, free energy of binding (ΔGbind) and inhibition constant (Ki), are analyzed and discussed. The compound 2 shows better inhibitory potency through uPa, than compound 1.

Exploring Molecular Docking algorithm for Lung Cancer Drug Discovery – A Case Study with RET Protein

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths across the globe.1.33% of all NSCLC cases occur due to an alteration in RET protein. Commonly occurring RET fusion partners include KIF5B, CCDC6, NCOA4, and TRIM33. Numerous multikinase inhibitors are active against rearranged RET. However, mutations in the RET-fusion protein can result in adverse effects in terms of drug resistance against NSCLC. In this context, molecular docking algorithm is certainly important to support the drug discovery pipelines. However, availability of huge number of algorithms in the literature limits the researchers to proceed further in drug discovery development. Thus, the present study focuses on finding the best docking algorithm among ArgusLab, PatchDock, AutoDock 4.0 and AutoDock Vina for drug discovery process against RET fusion cancers using Pearson’s correlation coefficient. We believe that our study will be a valuable source of information for carrying out further computational studies on RET fusion cancer, both mutant and wild type.

Epitope - based peptide vaccine against glycoprotein GPC precursor of Lujo virus using immunoinformatics approaches

BackgroundLujo virus (LUJV) is a highly fatal human pathogen belonging to the Arenaviridae family. Lujo virus causes viral hemorrhagic fever (VHF). An In silico molecular docking was performed on the GPC domain of Lujo virus in complex with the first CUB domain of neuropilin-2.The aim of this study is to predict effective epitope-based vaccine against glycoprotein GPC precursor of Lujo virus using immunoinformatics approaches.Methods and Materialsglycoprotein GPC precursor of Lujo virus Sequence was retrieved from NCBI. Different prediction tools were used to analyze the nominee’s epitopes in BepiPred-2.0: Sequential B-Cell Epitope Predictor for B-cell, T-cell MHC class II & I. Then the proposed peptides were docked using Autodock 4.0 software program.Results and ConclusionsThe proposed and promising peptides FWYLNHTKL and YMFSVTLCI shows a very strong binding affinity to MHC class I & II alleles with high population coverage for the world, South Africa and Sudan. This indicates a strong potential to formulate a new vaccine, especially with the peptide YMFSVTLCI which is likely to be the first proposed epitope-based vaccine against glycoprotein GPC of Lujo virus. This study recommends an in-vivo assessment for the most promising peptides especially FWYLNHTKL, YMFSVTLCI and LPCPKPHRLR.

In silico Assessment of Potential Leads Identified from Bauhinia rufescens Lam. as α-Glucosidase and α-Amylase Inhibitors

Aim: Natural products play a pivotal role in innovative drug discovery by providing structural leads for the development of new therapeutic agents against various diseases. The present study aims to focus on the in silico assessment of the therapeutic potential of antidiabetic phytoconstituents which were identified and isolated from the extracts of Bauhinia rufescens Lam., a medicinal plant traditionally used for various pharmacotherapeutic purposes. Methods: The physicochemical and pharmacokinetic parameters of the isolated thirty eight compounds were predicted using Swiss ADME web tool whereas OSIRIS Property Explorer was used for toxicity risk assessment and drug- likeliness. Twelve compounds were selected for docking on human α-glucosidase and α-amylase enzymes using Autodock 4.0 software. Results and Discussion: Eriodictyol was found to have the highest potential as an inhibitor against α-amylase with binding energy of -9.92 kcal/mol. Rutin was the most potent against α-glucosidase with binding energy of-9.15 kcal/mol. A considerable number of hydrogen bonds and hydrophobic interactions were computed between the compounds and the enzymes thereby making them energetically favorable and suggesting inhibition of these two enzymes as a plausible molecular mechanism for their antidiabetic effect. Conclusion: These two flavonoids could therefore be used as potential leads for structure- based design of new effective hypoglycemic agents.