Chemical Group Profiling, In Vitro and In Silico Evaluation of Aristolochia ringens on α-Amylase and α-Glucosidase Activity

Diabetes mellitus (DM) has become a global scourge, and there is a continuous search for novel compounds as viable alternatives to synthetic drugs which are often accompanied by severe adverse effects. Aristolochia ringens is among the scientifically implicated botanicals effective in the management of several degenerative diseases including DM. The current study evaluated the inhibitory mechanism(s) of root extract of A. ringens on α-amylase and α-glucosidase in vitro and in silico, while its constituents were characterized using liquid chromatography-mass spectrometric technique. The extract had concentration-dependent inhibitory effect on the study enzymes, and the inhibition compared well with that of standard drug (acarbose) with respective IC50 values of 0.67 mg/mL (α-amylase) and 0.57 mg/mL (α-glucosidase) compared with that of the extract (0.63 and 0.54 mg/mL). The extract competitively and uncompetitively inhibited α-amylase and α-glucosidase, respectively. Of the identified compounds, dianoside G (−12.4, −12.5 kcal/mol) and trilobine (−10.0, −10.0 kcal/mol) had significant interactions with α-amylase and α-glucosidase, respectively, while magnoflorine and asiatic acid also interacted keenly with both enzymes, with quercetin 3-O-glucuronide and strictosidine showing better affinity towards α-glucosidase. These observations are suggestive of involvement of these compounds as probable ligands contributing to antidiabetic potential of the extract. While studies are underway to demystify the yet to be identified compounds in the extract, the data presented have lent scientific credence to the acclaimed in vivo antidiabetic potential of the extract and suggested it as a viable source of oral hypoglycaemic agent.

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In silico studies of bacterial derived fatty acid as a potential inhibitor of 1FGE and 1BQO

Research Journal of Biotechnology ◽

10.25303/1612rjbt119124 ◽

2021 ◽

Vol 16 (12) ◽

pp. 119-124

Author(s):

S. Syed Chandini ◽

Sairam Mantri

Keyword(s):

Ligand Binding ◽

Stearic Acid ◽

In Silico ◽

In Vivo Studies ◽

Binding Interaction ◽

Standard Drug ◽

Synthetic Drugs ◽

Potential Inhibitor ◽

In Silico Studies

Thrombomodulin (TM) and matrix metalloproteinase (MMPs) are the major factors that are responsible for lung cancer. Hence, the identification of novel compounds inhibiting TM and MMPs is the challenging task for the scientists. Even though synthetic drugs were developed, their toxicity and offtarget limit their usage. The current study aims to investigate the molecular simulations for bacterial derived stearic acid to estimate the in silico anticancer activity against TM and MMPs protein as target compounds and the findings were correlated with the standard drug vorinostat. Using Lamarckian genetic algorithm, the TM and MMPs were energy minimized and docked with stearic acid and vorinostat using auto dock 4.2 and visualized in PyMol software. Protein and ligand binding analysis revealed that stearic acid interacts with the amino acids of MMPs residues of PHE83, SER212, ALA213 and ASN214. It interacts with the TMs with two amino acid residues i.e. CYS407 and GLU408. Hence, compared to vorinostat, stearic acid shows a higher binding affinity towards MMPs and slightly lower affinity towards TM proteinase. We conclude that the computational analysis of ligand binding interaction of stearic acid suggests that it could be a potential inhibitor of matrix metallo proteinase and is effective against thrombomodulin and can be considered as an anticancer agent by in vivo studies.

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COMPARATIVE EVALUATION OF IN VITRO ANTIOXIDANT AND IN VIVO HEPATOPROTECTIVE ACTIVITIES OF ETHANOLIC LEAF AND ROOT EXTRACTS OF CLEOME GYNANDRA

INDIAN DRUGS ◽

10.53879/id.56.04.11629 ◽

2019 ◽

Vol 56 (04) ◽

pp. 50-56

Author(s):

K Ravishankar ◽

Y.V.V.M. Lakshmi Prasanna ◽

G.V.N. Kiranmayi ◽

Keyword(s):

Carbon Tetrachloride ◽

Hepatoprotective Activity ◽

Root Extract ◽

Serum Glutamic Oxaloacetic Transaminase ◽

Root Extracts ◽

Cleome Gynandra ◽

Ic50 Values ◽

Ethanolic Leaf Extract

In vitro antioxidant and in vivo hepatoprotective activities of Cleome gynandra ethanolic leaf and root extracts were assessed. In vitro antioxidant activity was carried by DPPH, Nitric oxide, hydroxyl radical and phosphomolybdenum assays. Hepatoprotective activity was evaluated by Carbon tetrachloride (CCl4) induced hepatotoxicity in albino rats.The animals were divided into seven groups (Four test groups - Ethanolic Leaf and Root Extracts of Cleome gynandra of 100 mg/kg and 200 mg/kg, standard silymarin (100 mg/kg), toxic control-carbon tetrachloride and vehicle). On the eight day, the blood was collected and parameters like serum glutamic oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), Alkaline phosphatase (ALP) and Total bilirubin (TB) were estimated. Significant antioxidant status with good IC50 values similar to standard ascorbic acid was obtained. A significant decrease in liver enzymes was observed in test groups comparable to silymarin. From the results obtained, ethanolic leaf extract has contributed better hepatoprotection compared with root extract in experimental rats.

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In Vitro and In Vivo Effectiveness of Carvacrol, Thymol and Linalool against Leishmania infantum

Molecules ◽

10.3390/molecules24112072 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2072 ◽

Cited By ~ 11

Author(s):

Mohammad Reza Youssefi ◽

Elham Moghaddas ◽

Mohaddeseh Abouhosseini Tabari ◽

Ali Akbar Moghadamnia ◽

Seyed Mohammad Hosseini ◽

...

Keyword(s):

Mtt Assay ◽

Leishmania Infantum ◽

Standard Drug ◽

In Vivo Test ◽

Causative Agents ◽

Ic50 Values ◽

Vector Borne ◽

Effective Drugs

Background: One of the most important causative agents of visceral leishmaniasis (VL) is Leishmania infantum, which is mainly spread by Phlebotomus and Lutzomyia sandflies in the Old and New World, respectively. Novel and effective drugs to manage this neglected vector-borne disease are urgently required. In this study, we evaluated the toxicity of carvacrol, thymol and linalool, three common essential oil constituents, on amastigotes and promastigotes of L. infantum. Methods: in vitro experiments were performed by 24 h MTT assay. Carvacrol, thymol and linalool at concentrations ranging from 1.3 to 10 μg/mL were tested on promastigotes of L. infantum. For in vivo test, two groups of hamsters (Mesocricetus auratus) received 100 mg/kg of body weight/day of carvacrol and thymol as intraperitoneal injection on day 7 post-infection, followed by a 48 h later injection. The third group was treated with the glucantime as standard drug (500 mg/kg) and the last group (control) just received normal saline. On the 16th day, the number of parasites and histopathological changes in liver and spleen were investigated. Results: 24 h MTT assay showed promising antileishmanial activity of thymol and carvacrol, with IC50 values of 7.2 (48 μM) and 9.8 μg/mL (65 μM), respectively. Linalool at all concentrations did not affect L. infantum promastigote viability. In vivo toxicity data of carvacrol and thymol showed that the former at 100 mg/kg was the safest and most effective treatment with little side effects on the liver. Conclusions: Overall, thymol and carvacrol are highly promising candidates for the development of effective and safe drugs in the fight against VL.

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In-silico Molecular Docking and ADME/Pharmacokinetic Prediction Studies of Some Novel Carboxamide Derivatives as Anti-tubercular Agents

Chemistry Africa ◽

10.1007/s42250-020-00162-3 ◽

2020 ◽

Vol 3 (4) ◽

pp. 989-1000

Author(s):

Mustapha Abdullahi ◽

Shola Elijah Adeniji

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

In Silico ◽

Density Functional ◽

Docking Simulation ◽

Basis Set ◽

Hybrid Functional ◽

Standard Drug

AbstractMolecular docking simulation of thirty-five (35) molecules of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamide (IPA) with Mycobacterium tuberculosis target (DNA gyrase) was carried out so as to evaluate their theoretical binding affinities. The chemical structure of the molecules was accurately drawn using ChemDraw Ultra software, then optimized at density functional theory (DFT) using Becke’s three-parameter Lee–Yang–Parr hybrid functional (B3LYP/6-311**) basis set in a vacuum of Spartan 14 software. Subsequently, the docking operation was carried out using PyRx virtual screening software. Molecule 35 (M35) with the highest binding affinity of − 7.2 kcal/mol was selected as the lead molecule for structural modification which led to the development of four (4) newly hypothetical molecules D1, D2, D3 and D4. In addition, the D4 molecule with the highest binding affinity value of − 9.4 kcal/mol formed more H-bond interactions signifying better orientation of the ligand in the binding site compared to M35 and isoniazid standard drug. In-silico ADME and drug-likeness prediction of the molecules showed good pharmacokinetic properties having high gastrointestinal absorption, orally bioavailable, and less toxic. The outcome of the present research strengthens the relevance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis which could help the medicinal chemists and pharmaceutical professionals in further designing and synthesis of more potent drug candidates. Moreover, the research also encouraged the in vivo and in vitro evaluation study for the proposed designed compounds to validate the computational findings.

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Evaluation of 2-Thioxoimadazolidin-4-One Derivatives as Potent Anti-Cancer Agents through Apoptosis Induction and Antioxidant Activation: In Vitro and In Vivo Approaches

Molecules ◽

10.3390/molecules27010083 ◽

2021 ◽

Vol 27 (1) ◽

pp. 83

Author(s):

Mohamed S. Nafie ◽

Ahmed I. Khodair ◽

Hebat Allah Y. Hassan ◽

Noha M. Abd El-Fadeal ◽

Hanin A. Bogari ◽

...

Keyword(s):

Cell Cycle ◽

In Silico ◽

Hepg2 Cells ◽

Flow Cytometric Analysis ◽

Apoptosis Induction ◽

Rt Pcr ◽

Anti Cancer ◽

Ic50 Values

Background: Hepatocellular carcinoma (HCC) is one of the most widespread malignancies and is reported as the fourth most prevalent cause of cancer deaths worldwide. Therefore, we aimed to investigate the probable mechanistic cytotoxic effect of the promising 2-thioxoimidazolidin-4-one derivative on liver cancer cells using in vitro and in vivo approaches. The compounds were tested for the in vitro cytotoxic activity using MTT assay, and the promising compound was tested in colony forming unit assay, flow cytometric analysis, RT-PCR, Western blotting, in vivo using SEC-carcinoma and in silico to highlight the virtual mechanism of action. Both compounds 4 and 2 performed cytotoxic effects against HepG2 cells with IC50 values of 0.017 and 0.18 μM, respectively, compared to Staurosporine and 5-Fu as reference drugs with IC50 values of 5.07 and 5.18 µM, respectively. Compound 4 treatment revealed apoptosis induction by 19.35-fold (11.42% compared to 0.59% in control), arresting the cell cycle at G2/M phase. Moreover, studying gene expression that plays critical roles in cell cycle and apoptosis by RT-PCR demonstrated that compound 4 enhances the expression of the pro-apoptotic genes p53, PUMA, and Caspase 3, 8, and 9, and impedes the anti-apoptotic Bcl-2 gene in the HepG2 cells. It can also inhibit the PI3K/AKT pathway at both gene and protein levels, which was reinforced by the in silico predictions of the molecular docking simulations towards the PI3K/AKT proteins. Finally, in vivo study verified that compound 4 has a promising anti-cancer activity through activating antioxidant levels (CAT, SOD and GSH) and ameliorating hematological, biochemical, and histopathological findings.

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In silico screening leads to novel scaffolds with both antifungal and anti-NLRP3 inflammasome activity

Access Microbiology ◽

10.1099/acmi.cc2021.po0093 ◽

2021 ◽

Vol 3 (12) ◽

Author(s):

David Lowes ◽

Rand Al-waqfi ◽

Kirk Hevener ◽

Brian Peters

Keyword(s):

Nlrp3 Inflammasome ◽

In Silico ◽

Fungal Growth ◽

Hyphal Growth ◽

Acetohydroxyacid Synthase ◽

In Silico Screening ◽

Chemical Structures ◽

Ic50 Values

Due to structural similarities that exist between established inhibitors of the NLRP3-inflammasome, sulfonylureas Glyburide and MCC-950, and herbicidal-sulfonylureas, that specifically target fungal acetohydroxyacid synthase (AHAS), we sought to determine the potential for compounds to block both inflammation and inhibit fungal growth. In silico screening of ∼250,000 compounds was used to identify a prioritized list of chemical structures capable of inhibiting both targets. Prioritization of the top 1% of scores identified ∼70 compounds with a diverse set of scaffolds for testing in vitro. Selected hits were used to assess anti-inflammatory function in a THP-1 challenge model with LPS+ATP and resulting IC50 values were obtained. MIC and hyphal-growth assays were conducted to determine potential antifungal activity using media depleted of branched chain amino acids isoleucine and valine, to confirm on target AHAS inhibition. Identification of hits that exhibited low micromolar activity for NLRP3 and AHAS inhibition were selected for SAR study. In vitro testing of the analogs along with molecular docking led to increased knowledge for lead optimization of the potential hits. In silico screening has resulted in IC50 (IL-1β release) and MIC50 (fungal growth) values with low μM potency against several Candida species. In vivo validation will further confirm the potential of the scaffolds for further synthetic-modification for the rationale design of novel dual-purpose drugs

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Cocoa (Theobroma cacao L.) Seed Proteins’ Anti-Obesity Potential through Lipase Inhibition Using In Silico, In Vitro and In Vivo Models

Foods ◽

10.3390/foods9101359 ◽

2020 ◽

Vol 9 (10) ◽

pp. 1359

Author(s):

Luis Jorge Coronado-Cáceres ◽

Griselda Rabadán-Chávez ◽

Luis Mojica ◽

Blanca Hernández-Ledesma ◽

Lucía Quevedo-Corona ◽

...

Keyword(s):

In Silico ◽

Seed Proteins ◽

Inhibitory Effect ◽

Mean Value ◽

Intragastric Administration ◽

Degree Of Hydrolysis ◽

In Vivo Models ◽

Hydrolysis Of

The aim of this study was to determine the pancreatic lipase (PL) inhibitory effect of cocoa protein (CP) hydrolysates (CPH) using in silico and in vitro approaches, and an in vivo high-fat diet (HF) obese rat model. The results showed better theoretical affinity on PL for cocoa peptides EEQR, GGER, QTGVQ, and VSTDVNIE released from vicilin and albumins (−6.5, −6.3, −6.2, and −6.1 kcal/mol, respectively). Absorption, distribution, metabolism, and excretion (ADMET) prediction showed the human intestinal absorption (HIA) capacity of orlistat and eight cocoa peptides, demonstrating that they presented a low probability of toxicity with values lower than 0.6, while the orlistat has a high probability of hepatotoxicity with a mean value of 0.9. CPH (degree of hydrolysis of 55%) inhibited PL with an IC50 (concentration needed to inhibit 50% of enzyme activity) value of 1.38 mg/mL. The intragastric administration of 150 mg CP/kg/day to rats increased total lipids and triglycerides excretion in feces, ranging from 11% to 15% compared to the HF-diet. The HF + CP-diet also significantly decreased (p < 0.05) the apparent rate of fat absorption compared with the HF group. These results suggest that CP has anti-obesity potential by inhibiting PL, thus helping to prevent the development of non-communicable diseases.

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Synthesis and studies of thiazolidinedione–isatin hybrids as α-glucosidase inhibitors for management of diabetes

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0022 ◽

2021 ◽

Vol 13 (5) ◽

pp. 457-485

Author(s):

Ramandeep Kaur ◽

Rajnish Kumar ◽

Nilambra Dogra ◽

Ashok Kumar ◽

Ashok Kumar Yadav ◽

...

Keyword(s):

In Silico ◽

Binding Free Energy ◽

Biological Evaluation ◽

Free Energy Calculations ◽

Standard Drug ◽

Glucosidase Inhibitors ◽

Cytotoxicity Studies ◽

Cytotoxicity Assessment

Aim: Keeping in view the side effects associated with clinically used α-glucosidase inhibitors, novel thiazolidinedione–isatin hybrids were synthesized and evaluated by in vitro, in vivo and in silico procedures. Materials & methods: Biological evaluation, cytotoxicity assessment, molecular docking, binding free energy calculations and molecular dynamics studies were performed for hybrids. Results: The most potent inhibitor A-10 (IC50 = 24.73 ± 0.93 μM) was competitive in manner and observed as non-cytotoxic. A-10 possessed higher efficacy than the standard drug (acarbose) during in vivo biological testing. Conclusion: The enzyme inhibitory potential and safety profile of synthetic molecules was recognized after in vitro, in vivo, in silico and cytotoxicity studies. Further structural optimization of A-10 can offer potential hit molecules suitable for future investigations.

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Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl]-N-arylacetamides: An In Silico and Biochemical Approach

Molecules ◽

10.3390/molecules26103043 ◽

2021 ◽

Vol 26 (10) ◽

pp. 3043

Author(s):

Furqan Ahmad Saddique ◽

Sana Aslam ◽

Matloob Ahmad ◽

Usman Ali Ashfaq ◽

Muhammad Muddassar ◽

...

Keyword(s):

Blood Glucose ◽

Blood Glucose Level ◽

Glucose Level ◽

In Silico ◽

Inhibition Activity ◽

Standard Drug ◽

Chronic Disorder ◽

Ic50 Values ◽

Biochemical Approach

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 μM, respectively, which were better than the standard drug, acarbose (IC50 = 58.8 μM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.

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Interaction of Ligands for PET with the Dopamine D3 Receptor: In Silico and In Vitro Methods

Biomolecules ◽

10.3390/biom11040529 ◽

2021 ◽

Vol 11 (4) ◽

pp. 529

Author(s):

Chia-Ju Hsieh ◽

Aladdin Riad ◽

Ji Youn Lee ◽

Kristoffer Sahlholm ◽

Kuiying Xu ◽

...

Keyword(s):

In Silico ◽

Dopamine D3 Receptor ◽

D3 Receptor ◽

In Silico Studies ◽

Ic50 Values ◽

Pet Radiotracers ◽

Dopamine D3 ◽

Competition Assays

[18F]Fallypride and [18F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (D3R). In spite of their similar D3 affinities, the two PET ligands display very different properties for labeling the D3R in vivo: [18F]Fallypride is capable of binding to D3R under “baseline” conditions, whereas [18F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [18F]Fallypride is able to compete with synaptic dopamine for binding to the D3R, whereas [18F]FTP is not. The goal of this study was to conduct a series of docking and molecular dynamic simulation studies to identify differences in the ability of each molecule to interact with the D3R that could explain these differences with respect to competition with synaptic dopamine. Competition studies measuring the ability of each ligand to compete with dopamine in the β-arrestin assay were also conducted. The results of the in silico studies indicate that FTP has a weaker interaction with the orthosteric binding site of the D3R versus that of Fallypride. The results of the in silico studies were also consistent with the IC50 values of each compound in the dopamine β-arrestin competition assays. The results of this study indicate that in silico methods may be able to predict the ability of a small molecule to compete with synaptic dopamine for binding to the D3R.

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