ADME Prediction Research Articles

Inflammation inhibitory activity of green tea, soybean, and guava extracts during Sars-Cov-2 infection through TNF protein in cytokine storm

Coronavirus disease is caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) known as COVID-19. COVID-19 has caused the deaths of 6,541,936 people worldwide as of September 27th, 2022. SARS-CoV-2 severity is determined by a cytokine storm condition, in which the innate immune system creates an unregulated and excessive production of pro-inflammatory such IL-1, IL-6, NF Kappa B, and TNF alpha signaling molecules known as cytokines. The patient died due to respiratory organ failure and an acute complication because of the hyper-inflammation phenomenon. Green tea, soybean, and guava bioactive substances are well-known to act as anti-inflammation, and antioxidants become prospective COVID-19 illness candidates to overcome the cytokine storm. Our research aims to discover the bioactivity, bioavailability, and protein targets of green tea, soybean, and guava bioactive compounds as anti-inflammatory agents via the TNF inhibition pathway. The experiment uses in silico methods and harnesses the accessible datasets. Samples of 3D structure and SMILE identity of bioactive compounds were retrieved from the KNApSAck and Dr Duke databases. The QSAR analysis was done by WAY2DRUG web server, while the ADME prediction was performed using SWISSADME web server, following the Lipinsky rules of drugs. The target protein and protein-protein interaction were analyzed using STRING DB and Cytoscape software. Lastly, molecular docking was performed using Autodock 4.2 and visualization with BioVia Discovery Studio 2019. The identified study showed the potential of green tea, soybean, and guava’s bioactive compounds have played an important role as anti-inflammation agents through TNF inhibitor pathway.

β-Secretase-1: In Silico Drug Reposition for Alzheimer's Disease.

The β-secretase-1 enzyme (BACE-1) performs a key role in the production of beta-Amyloid protein (Aβ), which is associated with the development of Alzheimer's disease (AD). The inhibition of BACE-1 has been an important pharmacological strategy in the treatment of this neurodegenerative disease. This study aims to identify new potential candidates for the treatment of Alzheimer's with the help of in silico studies, such as molecular docking and ADME prediction, from a broad list of candidates provided by the DrugBank database. From this analysis, 1145 drugs capable of interacting with the enzyme with a higher coupling energy than Verubecestat were obtained, subsequently only 83 presented higher coupling energy than EJ7. Applying the oral route of administration as inclusion criteria, only 41 candidates met this requirement; however, 6 of them are associated with diagnostic tests and not treatment, so 33 candidates were obtained. Finally, five candidates were identified as possible BACE-1 inhibitors drugs: Fluphenazine, Naratriptan, Bazedoxifene, Frovatriptan, and Raloxifene. These candidates exhibit pharmacophore-specific features, including the indole or thioindole group, and interactions with key amino acids in BACE-1. Overall, this study provides insights into the potential use of in silico methods for drug repurposing and identification of new candidates for the treatment of Alzheimer's disease, especially those targeting BACE-1.

In Silico Analysis of Anti-Inflammatory and Antioxidant Properties of Bioactive Compounds from Crescentia cujete L.

Crescentia cujete is widely known as a medical plant with broad indigenous ethnomedicinal uses, including anti-inflammatory, and antioxidant. Despite being used for remedies and ethnomedicinal purposes, the benefits obtained from C. cujete still need to be fully utilized. The underwhelming studies on its pharmacological potential, bioactive compounds, and mechanism of action keep the pharmacological and new drug discovery progress of this plant slow. This study focuses on the incorporation of in silico analyses such as ADME prediction and molecular docking simulations on the bioactive compounds identified in the plant to assess their potential for antioxidant and anti-inflammatory applications. A comparison of the ADME properties and molecular docking scores showed that naringenin, pinocembrin, and eriodictyol had the most potential to act as inhibitors of the target proteins involved in inflammation and oxidation pathways against the positive controls.

Binding Analysis and Structure-Based Design of Tricyclic Coumarin-Derived MTHFD2 Inhibitors as Anticancer Agents: Insights from Computational Modeling.

Unfolded protein response (UPR)-dependent metabolic reprogramming diverts metabolites from glycolysis to mitochondrial 1C metabolism, highlighting pharmacological resistance to folate drugs and overexpression of certain enzymes. Methylenetetrahydrofolate dehydrogenase (MTHFD2) is a mitochondrial enzyme that plays a key role in 1C metabolism in purine and thymidine synthesis and is exclusively overexpressed in cancer cells but absent in most healthy adult human tissues. To the best of our knowledge, tricyclic coumarin-based compounds (substrate site binders) and xanthine derivatives (allosteric site binders) are the only selective inhibitors of MTHFD2 reported until the present date. The current study aims at the investigation of the available structural data of MTHFD2 in complex with potent and selective inhibitors that occupy the substrate binding site, further providing insights into binding mode, key protein-ligand interactions, and conformational dynamics, that correspond to the experimental binding affinities and biological activities. In addition, we carried out structure-based drug design on the substrate binding site of MTHFD2, by exploiting the cocrystal structure of MTHFD2 with the tricyclic coumarin-based inhibitor. The structure-based drug design campaign involves R-group enumeration, bioisostere replacement, molecular docking, ADME prediction, MM-GBSA binding free energy calculations, and molecular dynamics simulations, that led to a small library of new and potential compounds, capable of selectively inhibiting MTHFD2. The results reported herein are expected to benefit medicinal chemists working on the development of selective MTHFD2 inhibitors for cancer treatment, although experimental validation by biochemical and/or pharmacokinetic assays is required to substantiate the outcomes of the study.

Investigation of Neolamarckia cadamba phytoconstituents against SARS-CoV-2 3CL Pro: An In-Silico Approach

In present study, the inhibitory potential of Neolamarckia cadamba phytoconstituents was investigated against SARS-CoV-2 3CL protease (3CL pro) (PDB ID: 6M2N). Molecular docking was analyzed using AutoDock Vina software by setting the grid parameter as X= -33.163, Y= -65.074 and Z= 41.434 with dimensions of the grid box 25 × 25 × 25 Å. Remdesivir was taken as the standard for comparative analysis along with inhibitor 5, 6, 7-trihydroxy-2-phenyl-4H-chromen-4-one. Furthermore, the exploration of 2 D Hydrogen-bond interactions was performed by Biovia Discovery Studio 4.5 program to identify the interactions between an amino acid of target and ligand followed by assessment of physicochemical properties using Lipinski’s rule and Swiss ADME database. The decent bonding scores of secondary metabolites owing to hydrogen bonding with catalytic residues suggest the effectiveness of these phytochemicals towards 3CLpro. The results are further consolidated positively by Lipinski’s rule and Swiss ADME prediction. Thus reasonably, observations with docking studies suggest possibility of phytochemicals from Neolamarckia cadamba to inhibit the 3CLpro and consequently would be explored further as agents for preventing COVID-19.

Synthesis, Spectral Characterization, In silico Docking and ADME Prediction and Biological Evaluation of Novel Piperidin-4-one Derivatives

Abstract: A novel series of 2, 6-diaryl-3-(4-methylpiperazin-1-yl) piperidin-4-one (2a-2f) derivatives were synthesized. All the synthesized compounds were characterized by FT-IR, NMR, Mass spectrum, and CHN analysis. NMR spectral analyses were performed unambiguously by their one-dimensional (1H NMR and 13C NMR) and two-dimensional (1H-1H COSY and 1H-13C HSQC) NMR. From the NMR spectral data, the compounds (2a-2f) were found to have normal chair conformation with an equatorial orientation of all the phenyl groups at C-2 and C-6 and the piperazine ring at C-3. The target compounds 2a-2f were subjected to insilico docking and ADME prediction. From the result of insilico docking study, compound 2d showed a good docking score (-8.2 kcal/mol) compared to the standard drug ciprofloxacin (-7.8 kcal/mol). The synthesized piperidine-4-one compounds (2a-2f) demonstrated good to moderate activity against gram-positive and gram-negative strains. From the result of insilico ADME prediction, most of the compound exhibited good drug score and good drug likeness property.

Antioxidant and Anticholinesterase Potentials of Novel 4,6-Dimethoxyindole based Unsymmetrical Azines: Synthesis, Molecular Modeling, In Silico ADME Prediction and Biological Evaluations

Chemically and biologically important -C = N-N = C- diimine linkage was used to build unsymmetrical azine systems with indole heterocyclic backbone and substituted aromatic carbaldehydes. Ten novel compounds 7a-j were synthesized by the Schiff base reaction of 4,6-dimethoxyindole-7-hydrazone 5 and a range of substituted carbaldehydes 6a-j with high yields and purities. The biological study was directed to identify the antioxidant potentials due to the expected electronic delocalization capability of designated linkage which is important for possible hydrogen or electron donation. The three different assays, namely DPPH free radical scavenging, ABTS cationic radical decolarization and CUPRAC (cupric reducing antioxidant capacity) were employed to detect the antioxidant properties. The antioxidant potentials were found to be moderate for ABTS and CUPRAC assays and the compound 7j was the most potent candidate for all the antioxidant assays. More importantly, the anticholinesterase properties were investigated by acetylcholinesterase (ACh) and butyrylcholinesterase (BCh) enzyme inhibition assays. The molecular docking studies were also carried out to determine the possible poses of ligands 7a-j in binding sites of enzymes and ligand-residue interactions. The synthesized compounds were found to be more effective for the anticholinesterase activity with three promising candidates 7d, 7h and 7j in the case of BChE inhibitions. The compound 7h was determined as the best candidate with the comparable IC50 values for AChE and better inhibition potency for BChE with 7j. A range of hydrophobic and hydrophilic interactions were detected for the designated compound 7h and 7j through different amino acid residues and the computational results were found to be compatible with the biological counterparts.

Synthesis, molecular docking and ADMET studies of bis-benzimidazole-based thiadiazole derivatives as potent inhibitors, in vitro α-amylase and α-glucosidase

Different research synthetic methods have been developed recently for the synthesis of bis-benzimidazole analogs to investigate various biological significances. In this present study, an attempt was made to synthesize a new series of bis-benzimidazole analogs in a fast and efficient method. A variety of spectroscopic techniques, including 13C NMR, 1H NMR, and HREI-MS, were used to establish the existence of every synthesized scaffold. Molecular docking profiles were also carried out to ascertain the binding interactions of the compounds. All derivatives (1–18) were evaluated for their biological potential toinvestigate the inhibitory activity of α-amylase and α-glucosidase through SAR study. Almost all derivatives were found to be engaged in a highly promising activity when compared to referenced drug acarbose (IC50 = 8.24 ± 0.08 µM), in this regard among the tested series analog 9 (IC50 = 0.10 ± 0.50 and 0.20 ± 0.50 µM respectively), showed excellent activity. Moreover, ADME predictions were also studied for potent compounds, exhibited drug like properties.

Wang-OSO3H catalyzed one-pot sonochemical synthesis of 1,2,4-benzothiadiazine-1,1-dioxide derivatives: Their in silico / in vitro assessments against MtbCM

The sonochemical synthesis, in silico assessment and in vitro MtbCM inhibitory activities of a series of 1,2,4-benzothiadiazine-1,1-dioxide derivatives are described. These compounds were synthesized via a one-pot two-step sonochemical method involving the Wang-OSO3H catalyzed reaction of 2-aminobenzenesulfonamide with aldehydes followed by treatment with NaHSO3 in the same pot. The reaction proceeded at room temp in pure water affording the desired products in good yields. The use of heterogeneous catalyst, common oxidant, water as a solvent and ultrasound as the source of green energy in addition to the mild conditions, shorter reaction time and simple operational procedure are the key features of this methodology. In silico studies suggested that most of the synthesized compounds interacted with the external surface pockets of the MtbCM (PDB: 2FP2) active site cavity. Indeed, a curved loop site was noted where these compounds were binding and aligned. Three compounds e.g. 3c, 3d and 3e interacted well with MtbCM via the -NHSO2- moiety of their 2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide ring showing a common H-bond with SER70. They also showed good (55–63%) inhibition of MtbCM in vitro when tested at 10 µM. According to the SAR study a 4-substututed phenyl ring was preferred over a 3- or 2-substutited phenyl moiety at the C-2 position and the 4-MeOC6H4 substituent at this position was most effective in terms of activity. On the other hand, mediocre to low activity was observed when a heteroaryl ring or the bulky 2-naphthyl moiety was present at the C-2 position. Based on in silico and in vitro studies along with the ADME predictions the 1,2,4-benzothiadiazine-1,1-dioxide derivatives 3c, 3d and 3e emerged as pre-hits for further pharmacological evaluations.

In Silico Study of Monascus sp. Pigment Derivatives as Anticardiovascular Candidate

Background: Cardiovascular disease is the leading cause of death in the world. The therapeutic activity of Monascus sp. pigment can act as an anticardiovascular agent. Research on Monascus sp. pigment is rapidly developing, including the discovery of new pigments, the methods used, and their identification. Currently, there are 57 dyestuff compounds that have been successfully isolated from Monascus molds. So, researchers conducted an in-silico study of Monascus sp. Objective: To determine whether it can have better interactions and activities as an anticardiovascular medicine candidate. Method: PAK1 is used as a receptor for anticardiovascular drugs. 57 test compounds were carried out for ligand preparation and application of Lipinski's rule of five by using MarvinSketch software, ADME prediction and toxicity testing using PreADMET, the docking process using Autodock tools, and visualization using Discovery Studio. Results: The results of the docking analysis are seen from the values of binding affinity consecutively. compound R3 (-8.74 kcal/mol), red shandong (-8.16 kcal/mol), and monaphilol (-8.14 kcal/mol) are lower than the comparison compound bisoprolol (-6.44 kcal/mol), which shows that the three compounds have better interactions than the comparison compounds. Conclusion: Derivative compounds from Monascus sp. Pigment are predicted to have better interactions and can be used as anticardiovascular medicine candidates. Keywords: Monascus sp., pigment, anticardiovascular, in silico, PAK1, ADME, and toxicity

Cheminformatics study of some indole compounds through QSAR modeling, ADME prediction, molecular docking, and molecular dynamic simulation to identify novel inhibitors of HCV NS5B protease

The hepatitis C virus is a viral disease that causes cirrhosis and hepatocellular carcinoma in the liver. Since the virus's discovery, significant therapeutic advances have been made. Notwithstanding, its upsurge necessitates the development of novel approaches to combating this disease. Recent studies have seen a rise in the value of plant compounds in the establishment of novel, efficient, and cost-efficient anti-HCV medications. These factors have motivated us to continuously search for novel, potent anti-HCV inhibitors, ideally with mechanisms different from those used in conventional medicine. Several filtrations processes including ADMET, molecular docking, and molecular dynamics (MD) simulation were used to choose potent hits from plant molecules deposited in the PubChem database. The binding kinetics were explored using MD simulation studies performed for 100 ns using GROMACS-2018.1. which was done to validate and supplement the findings of the virtual screening. The selected hits (with PubChem CID of 3,560,948 and 4,754,183) had preferable molecular traits that suggested they might work well as HCV inhibitors and are term as effective potential hits. The MD study confirmed the stability of the identified hit with a binding energy of −111.724 ( ± 81.668) kj/mol and mechanisms different from the FDA-approved drug (sofosbuvir) used as a reference with a binding energy of −106.132 ( ± 78.008) kj/mol. This approach could aid in the establishment and identification of novel inhibitors in pharmaceutical discovery. Experimental assessments could indeed ascertain as to if the identified molecule can be employed as an anti-HCV drug to address the ailment and confirm the reliability of our in-silico studies.

Biochemoinformatics Study of Chemical Constituents of Apium graveolens, Aloe vera, and Nigella sativa as Antidiabetic Herbal

Background: Celery (Apium graveolens), Aloe vera, and black cumin (Nigella sativa) are reported to have antidiabetic activity from various studies. The present study aimed to predict the active constituents of A. graveolens, A. vera, and N. sativa that able to interact to macromolecular targets of the antidiabetic agent, i.e. dipeptidyl-peptidase 4 enzyme (DPP4), protein tyrosine phosphatase-1B (PTP1B), glucokinase, as well as α-glucosides through molecular docking analysis, and predict their pharmacokinetic profiles. Methods: The chemical structures of each plant (from KNApSAcK webserver) had undergone molecular docking simulation using Autodock Vina in PyRx. ADME prediction was conducted by using SwissADME webserver. Results: The results showed that apiin (A. graveolens), rutin (A. vera), and quercetin 3-glucosyl-(12)-galactosyl-(12)-glucoside (N. sativa) had the best interaction to DPP4. While 4,8,5'-Trimethylpsoralen (A. graveolens), 8-C-Glucosyl-(2'-O-cinnamoyl)-7-O-methylaloediol A (A. vera), and nigellidine 4-O-sulfite (N. sativa) had the best interaction to PTP1B. Cyanidin 3-[6-(6-p-coumarylglucosyl)-2-xylosylgalactoside] (A. graveolens), isoaloeresin D (A. vera), and nigellidine 4-O-sulfite (N. sativa) had the best interaction to glucokinase. Luteolin (A. graveolens), aloeresin E (Aloe vera), and quercetin 3-glucosyl-(12)-galactosyl-(12)-glucoside (N. sativa) had the best interaction to α-glucosidase. Additionally, nigellidine 4-O-sulfite and 4,8,5'-trimethylpsoralen were predicted to have good bioavailability score on SwissADME. Conclusions: A. graveolens, A. vera, and N. sativa contains chemical constituents those were predicted to havo good interaction to molecular target of the antidiabetics therapy, i.e. DPP4, PTP1B, glucokinase, and α-glucosides

An in silico investigation of 1,2,4-triazole derivatives as potential antioxidant agents using molecular docking, MD simulations, MM-PBSA free energy calculations and ADME predictions

In this study, we’ve performed computable studies of previously synthesized 1,2,4-triazole derivatives by virtual screening due to antioxidant activity. Six enzymes responsible for regulating oxidative stress were selected as key targets. One hundred and twelve compounds were subjected to semi-flexible molecular docking, which resulted in the selection of 23 substances based on binding energy for further ADME analysis. In addition, molecular dynamics studies of complexes with the best docking scores, reference complexes and apo-proteins were described in detail here. The results of 100 ns modeling (RMSD, RMSF, SASA, Rg, PCA) indicate great stability during the formation of complexes with our two potential compounds, as well as favorable binding energy, which was determined theoretically by means of the MM/PBSA method, thereby increase the likelihood of their acting as promising inhibitors of selected enzymes.

Novel hybrids of quinoline with pyrazolylchalcones as potential antimalarial agents: Synthesis, biological evaluation, molecular docking and ADME prediction

A novel series of pyrazolyl chalcones containing quinoline scaffold, 5 a-v has been synthesized by Claisen Schimdt condensation of aromatic acetophenone with 1-(4-methylquinolin-2-yl)-3-aryl-1H-pyrazole-4-carbaldehyde in quantitative yield. The compounds were characterized using IR, NMR, MS and elemental analysis. An E-configuration about CC ethylenic bond was determined using 1H NMR spectroscopy. These compounds exhibited significant antimalarial potential against CQ-sensitive and CQ-resistant strain of Plasmodium falciparum. Structure activity relationship has also been established based on outcomes of in vitro schizont inhibition assay. Compound 5u, (Z)-3-(1-(4-methylquinolin-2-yl)-3-p-tolyl-1H-pyrazol-4-yl)-1-p-tolylprop-2-en-1-one, was found to be the most potent among the series of synthetic analogues. In vivo, it demonstrated significant parasitemia suppression of 78.01% at a dose of 200 mg/kg against P. berghei in infected mice without any mortality in 7 days. In silico molecular docking study revealed that this compound 5u bound to the active site of cysteine protease falcipain-2 enzyme. Furthermore, in silico ADME studies, were also performed and physicochemical qualifications of the title compounds were determined. The biological outcomes of newer heterocyclic compounds may pave the new paths for researchers in development of potential antimalarial agents.

Novel 7-Chloro-4-aminoquinoline-benzimidazole Hybrids as Inhibitors of Cancer Cells Growth: Synthesis, Antiproliferative Activity, in Silico ADME Predictions, and Docking.

In this study, new 7-chloro-4-aminoquinoline-benzimidazole compounds were synthesized and characterized by NMR, MS, and elemental analysis. These novel hybrids differ in the type of linker and in the substituent on the benzimidazole moiety. Their antiproliferative activities were evaluated on one non-tumor (MDCK1) and seven selected tumor (CaCo-2, MCF-7, CCRF-CEM, Hut78, THP-1, and Raji) cell lines by MTT test and flow cytometry analysis. The compounds with different types of linkers and an unsubstituted benzimidazole ring, 5d, 8d, and 12d, showed strong cytotoxic activity (the GI50 ranged from 0.4 to 8 µM) and effectively suppressed the cell cycle progression in the leukemia and lymphoma cells. After 24 h of treatment, compounds 5d and 12d induced the disruption of the mitochondrial membrane potential as well as apoptosis in HuT78 cells. The drug-like properties and bioavailability of the compounds were calculated using the Swiss ADME web tool, and a molecular docking study was performed on tyrosine-protein kinase c-Src (PDB: 3G6H). Compound 12d showed good solubility and permeability and bound to c-Src with an energy of -119.99 kcal/mol, forming hydrogen bonds with Glu310 and Asp404 in the active site and other residues with van der Waals interactions. The results suggest that compound 12d could be a leading compound in the further design of effective antitumor drugs.

Unveiling the inhibitory mechanism of aureusidin targeting xanthine oxidase by multi-spectroscopic methods and molecular simulations.

Xanthine oxidase (XO) is a key target for gout treatment. Great efforts have been made towards the discovery and development of new XO inhibitors. Aureusidin (AUR), a natural compound, emerges as the second reported XO inhibitor with an aurone skeleton with an IC50 value of 7.617 ± 0.401 μM in vitro. The inhibitory mechanism of AUR against XO was explored through enzyme kinetic studies, multi-spectroscopic methods, computer simulation techniques, and ADME prediction. The results showed that AUR acts as a rapid reversible and mixed-type XO inhibitor and its binding to XO was driven by hydrogen bonding and hydrophobic interaction. Moreover, AUR presented a strong fluorescence quenching effect through a static quenching process and induced a conformation change of XO. Its binding pattern with XO was revealed through molecular docking, and its affinity toward XO was enhanced through interactions with key amino acid residues in the active pocket of XO. Further, AUR demonstrated good stability and pharmacokinetic behavior properties in molecular dynamics simulation and ADME prediction. In short, the current work clarified in depth the inhibitory mechanism of AUR on XO firstly and then provided fresh insights into its further development as a natural potent XO inhibitor with aurone skeleton.

Naphthyl bearing 1,3,4-thiadiazoleacetamides targeting the parasitic folate pathway as anti-infectious agents: in silico, synthesis, and biological approach.

Malaria is still a complex and lethal parasitic infectious disease, despite the availability of effective antimalarial drugs. Resistance of malaria parasites to current treatments necessitates new antimalarials targeting P. falciparum proteins. The present study reported the design and synthesis of a series of a 2-(4-substituted piperazin-1-yl)-N-(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl)acetamide hybrids for the inhibition of Plasmodium falciparum dihydrofolate reductase (PfDHFR) using computational biology tools followed by chemical synthesis, structural characterization, and functional analysis. The synthesized compounds were evaluated for their in vitro antimalarial activity against CQ-sensitive PfNF54 and CQ-resistant PfW2 strain. Compounds T5 and T6 are the most active compounds having anti-plasmodial activity against PfNF54 with IC50 values of 0.94 and 3.46 μM respectively. Compound T8 is the most active against the PfW2 strain having an IC50 of 3.91 μM. Further, these active hybrids (T5, T6, and T8) were also evaluated for enzyme inhibition assay against PfDHFR. All the tested compounds were non-toxic against the Hek293 cell line with good selectivity indices. Hemolysis assay also showed non-toxicity of these compounds on normal uninfected human RBCs. In silico molecular docking studies were carried out in the binding pocket of both the wild-type and quadruple mutant Pf-DHFR-TS to gain further insights into probable modes of action of active compounds. ADME prediction and physiochemical properties support their drug-likeness. Additionally, they were screened for antileishmanial activity against L. donovani promastigotes to explore broader applications. Thus, this study provides molecular frameworks for developing potent antimalarials and antileishmanial agents.

In silico and invitro studies of potential inhibitors against Dengue viral protein NS5 Methyl Transferase from Ginseng and Notoginseng.

Dengue is a potentially deadly tropical infectious disease transmitted by mosquito vector Aedes aegypti with no antiviral drug available to date. Dengue NS5 protein is crucial for viral replication and is the most conserved among all four Dengue serotypes, making it an attractive drug target. Both Ginseng and Notoginseng extracts and isolates have been shown to be effective against various viral infections yet against Dengue Virus is understudied. We aim to identify potential inhibitors against Dengue NS5 Methyl transferase from small molecular compounds found in Ginseng and Notoginseng. A molecular docking model of Dengue NS5 Methyl transferase (MTase) domain was tested with decoys and then used to screen 91 small molecular compounds found in Ginseng and Notoginseng followed by Molecular dynamics simulations and the per-residue free energy decompositions based on molecular mechanics/Poisson-Boltzmann (generalised Born) surface area (MM/PB(GB)SA) calculations of the hit. ADME predictions and drug-likeness analyses were discussed to evaluate the viability of the hit as a drug candidate. To confirm our findings, invitro studies of antiviral activities against RNA and a E protein synthesis and cell toxicity were carried out. The virtual screening resulted in Isoquercitrin as a single hit. Further analyses of the Isoquercitrin-MTase complex show that Isoquercitrin can reside within both of the NS5 Methyl Transferase active sites; the AdoMet binding site and the RNA capping site. The Isoquercitrin is safe for consumption and accessible on multikilogram scale. Invitro studies showed that Isoquercitrin can inhibit Dengue virus by reducing viral RNA and viral protein synthesis with low toxicity to cells (CC50>20μM). Our work provides evidence that Isoquercitrin can serve as an inhibitor of Dengue NS5 protein at the Methyl Transferase domain, further supporting its role as an anti-DENV agent.

Allosteric modulation on specific gene mutated Vitamin D receptor by essential PUFAs and its distinct molecular effects on type 2 diabetes mellitus

A serious health threat affecting the T2DM group is evident more cases T2DM are diagnosed. In this research, we choose to research into all of this possible mechanism of 3T3-L1 Cell lines and Molecular Docking studies Schrodinger software identified Vitamin D, Omega-3, and 6 PUFAs (EPA DHA & AA) Compounds of hydrophilic and hydrophobic pocket throughout molecular modeling besides T2DM. A group of three analog VDRs is being developed for discovery treatment with T2DM. Its use as it was agreed to run a molecular cell culture and docking study. Recognize the binding method involving the compound in T2DM through ADME prediction. The molecular dynamics simulation was enhanced by confirmation of the strength of the possible composite binding. Based on the computational results, the Omega-3 and 6 PUFAs compound encourages energy interaction. The composite contains an in vitro anti-diabetic activity; the compounds have clearly shown that they are active on T2DM. Our studies provide vital information on the findings of the bimolecular T2DM inhibitors.

Swiss ADME predictions of pharmacokinetics and drug-likeness properties of secondary metabolites present in Trigonella foenum-graecum

Swiss ADME predictions of pharmacokinetics and drug-likeness properties of secondary metabolites present in Trigonella foenum-graecum