scholarly journals Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SRA, Molecular Docking, and ADMET Analyses

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3121
Author(s):  
Nahed N. E. El-Sayed ◽  
Taghreed M. Al-Otaibi ◽  
Mona Alonazi ◽  
Vijay H. Masand ◽  
Assem Barakat ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Biological Activities ◽  
Sudden Cardiac Arrest ◽  
Structural Features ◽  
In Silico Admet ◽  
Lovo Cells ◽  
Hct 116 ◽  
Cox 2

The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX‑2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff’s bases as: antibacterial, COX‑2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.

scholarly journals Chemical Profiles and Pharmacological Properties with in Silico Studies on Elatostema papillosum Wedd

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 809 ◽  
Author(s):  
Md. Zia Uddin ◽  
Arkajyoti Paul ◽  
Ahmed Rakib ◽  
Saad Ahmed Sami ◽  
Shafi Mahmud ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Serotonin Receptor ◽  
Computational Study ◽  
Biological Activities ◽  
Binding Affinities ◽  
In Silico Studies ◽  
Cox 2 ◽  
Cox 1

The current study attempted, for the first time, to qualitatively and quantitatively determine the phytochemical components of Elatostema papillosum methanol extract and their biological activities. The present study represents an effort to correlate our previously reported biological activities with a computational study, including molecular docking, and ADME/T (absorption, distribution, metabolism, and excretion/toxicity) analyses, to identify the phytochemicals that are potentially responsible for the antioxidant, antidepressant, anxiolytic, analgesic, and anti-inflammatory activities of this plant. In the gas chromatography-mass spectroscopy analysis, a total of 24 compounds were identified, seven of which were documented as being bioactive based on their binding affinities. These seven were subjected to molecular docking studies that were correlated with the pharmacological outcomes. Additionally, the ADME/T properties of these compounds were evaluated to determine their drug-like properties and toxicity levels. The seven selected, isolated compounds displayed favorable binding affinities to potassium channels, human serotonin receptor, cyclooxygenase-1 (COX-1), COX-2, nuclear factor (NF)-κB, and human peroxiredoxin 5 receptor proteins. Phytol acetate, and terpene compounds identified in E. papillosum displayed strong predictive binding affinities towards the human serotonin receptor. Furthermore, 3-trifluoroacetoxypentadecane showed a significant binding affinity for the KcsA potassium channel. Eicosanal showed the highest predicted binding affinity towards the human peroxiredoxin 5 receptor. All of these findings support the observed in vivo antidepressant and anxiolytic effects and the in vitro antioxidant effects observed for this extract. The identified compounds from E. papillosum showed the lowest binding affinities towards COX-1, COX-2, and NF-κB receptors, which indicated the inconsequential impacts of this extract against the activities of these three proteins. Overall, E. papillosum appears to be bioactive and could represent a potential source for the development of alternative medicines; however, further analytical experiments remain necessary.

Synthesis and characterization of steroidal heterocyclic compounds, DNA condensation and molecular docking studies and their in vitro anticancer and acetylcholinesterase inhibition activities

RSC Advances ◽  
2015 ◽  
Vol 5 (93) ◽  
pp. 75964-75984 ◽  
Author(s):  
Abad Ali ◽  
Mohd Asif ◽  
Hena Khanam ◽  
Ashraf Mashrai ◽  
Mohd Asif Sherwani ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Heterocyclic Compounds ◽  
Biological Activities ◽  
Docking Studies ◽  
Dna Condensation ◽  
Acetylcholinesterase Inhibition ◽  
Synthesis And Characterization ◽  
Efficient Approach

A facile and efficient approach for the synthesis of steroidal heterocyclic compounds (4–12) has been performed. Furthermore, these newly synthesized compounds were evaluated for their various biological activities.

Design, Synthesis, Characterization and in silico molecular docking studies and in vivo anti-inflammatory Activity of Pyrazoline clubbed Thiazolinone Derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Deepak Kumar Singh ◽  
Mayank Kulshreshtha ◽  
Yogesh Kumar ◽  
Pooja A Chawla ◽  
Akash Ved ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Biological Activities ◽  
Inflammatory Activity ◽  
Standard Drug ◽  
Docking Score ◽  
Chemical Structures ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

1'-methylspiro[indoline-3,4'-piperidine] Derivatives: Design, Synthesis, Molecular Docking and Anti-tumor Activity Studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Junjian Li ◽  
Lianbao Ye ◽  
Yuanyuan Wang ◽  
Ying Liu ◽  
Xiaobao Jin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Active Sites ◽  
Biological Activities ◽  
Significant Inhibition ◽  
Alkaline Condition ◽  
Discovery Studio ◽  
Hela Cell Lines ◽  
Antiproliferative Activities

Background: Spirocyclic indoline compounds widely exist in numerous natural products with good biological activities and some drug molecules in many aspects. In recent years, it has attracted extensive attention as potent anti-tumor agents in the fields of pharmacology and chemistry. Objective: In this study, we focused on designing and synthesizing a set of novel 1'-H-spiro[indole-3,4'-piperidine] derivatives, which were evaluated by preliminary bioactivity experiment in vitro and molecular docking. Method: The key intermediate 1'-methylspiro[indoline-3,4'-piperidine] (B4) reacted with benzenesulfonyl chloride with different substituents under alkaline condition to obtain its sulfonyl derivatives (B5-B10). We evaluated their antiproliferative activities against A549, BEL-7402 and HeLa cells by MTT assay. We performed the CDOCKER module in Discovery Studio 2.5.5 software for molecular modeling of compound B5, and investigated the binding of compound B5 with the target proteins from PDB database. Results: The results indicated that compounds B4-B10 exhibited good antiproliferative activities against the above three types of cells, in which compound B5 with chloride atom as electron-withdrawing substituent on a phenyl ring showed the highest potency against BEL-7402 cells (IC50=30.03±0.43 μg/mL). By binging of the prominent bioactive compound B5 to CDK, c-Met, EGFR protein crystals, The binding energy of B5 with these three types receptors are -44.3583 kcal/mol, - 38.3292 kcal/mol, -33.3653 kcal/mol respectively. Conclusion: Six 1'-methylspiro[indoline-3,4'-piperidine] derivatives were synthesized and evaluated against BEL-7402, A- 549, HeLa cell lines. Compound B5 showed significant inhibition on BEL-7402 cell lines. Molecular docking revealed that B5 showed good affinity by the good fitting between B5 and these three targets with amino acid residues in active sites which encourage us to conduct further evaluation such as the kinase experiment.

Action of Thioglycosides of 1,2,4-Triazoles and Imidazoles on the Oxidative Stress and Glycosidases in Mice with Molecular Docking

2019 ◽  
Vol 16 (6) ◽  
pp. 696-710
Author(s):  
Mahmoud Balbaa ◽  
Doaa Awad ◽  
Ahmad Abd Elaal ◽  
Shimaa Mahsoub ◽  
Mayssaa Moharram ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Docking ◽  
Active Sites ◽  
Biological Activities ◽  
Imidazole Ring ◽  
Quantitative Structure Activity Relationship ◽  
Binding Interaction ◽  
Qsar Study

Background: ,2,3-Triazoles and imidazoles are important five-membered heterocyclic scaffolds due to their extensive biological activities. These products have been an area of growing interest to many researchers around the world because of their enormous pharmaceutical scope. Methods: The in vivo and in vitro enzyme inhibition of some thioglycosides encompassing 1,2,4- triazole N1, N2, and N3 and/or imidazole moieties N4, N5, and N6. The effect on the antioxidant enzymes (superoxide dismutase, glutathione S-transferase, glutathione peroxidase and catalase) was investigated as well as their effect on α-glucosidase and β-glucuronidase. Molecular docking studies were carried out to investigate the mode of the binding interaction of the compounds with α- glucosidase and β -glucuronidase. In addition, quantitative structure-activity relationship (QSAR) investigation was applied to find out the correlation between toxicity and physicochemical properties. Results: The decrease of the antioxidant status was revealed by the in vivo effect of the tested compounds. Furthermore, the in vivo and in vitro inhibitory effects of the tested compounds were clearly pronounced on α-glucosidase, but not β-glucuronidase. The IC50 and Ki values revealed that the thioglycoside - based 1,2,4-triazole N3 possesses a high inhibitory action. In addition, the in vitro studies demonstrated that the whole tested 1,2,4-triazole are potent inhibitors with a Ki magnitude of 10-6 and exhibited a competitive type inhibition. On the other hand, the thioglycosides - based imidazole ring showed an antioxidant activity and exerted a slight in vivo stimulation of α-glucosidase and β- glucuronidase. Molecular docking proved that the compounds exhibited binding affinity with the active sites of α -glucosidase and β-glucuronidase (docking score ranged from -2.320 to -4.370 kcal/mol). Furthermore, QSAR study revealed that the HBD and RB were found to have an overall significant correlation with the toxicity. Conclusion: These data suggest that the inhibition of α-glucosidase is accompanied by an oxidative stress action.

Evaluation of Pyrano[3,2 C] Quinoline Analogues as Anticancer Agents

2019 ◽  
Vol 19 (10) ◽  
pp. 1285-1292 ◽  
Author(s):  
Kuldip D. Upadhyay ◽  
Anamik K. Shah
Keyword(s):  
Anticancer Agents ◽  
Human Cancer ◽  
Biological Activities ◽  
Cytotoxic Agents ◽  
Tumor Growth Inhibition ◽  
Mice Model ◽  
One Pot ◽  
Aryl Ring ◽  
Hct 116

Background: Quinoline analogues exhibited diversified biological activities depending on the structure type. A number of natural products with pyrano[3,2-c]quinolone structural motifs and patented chromenes were reported as promising cytotoxic agents. Objective: The present study is aimed to evaluate a new series of pyrano[3,2-c]quinoline scaffolds derived from the fusion of bioactive quinolone pharmacophore with structurally diverse aryl substituted chromene for its cytotoxicity. Methods: A library of pyrano[3,2-c]quinoline analogues was prepared from one-pot multi component synthesis using various aromatic aldehydes, malononitrile and 2,4-dihydroxy-1-methylquinoline. The new synthetics were primarily screened for its cytotoxicity (IC50) against different human cancer cell lines in vitro. The promising synthetics were further evaluated in vitro for their potency against different kinase activity. The promising compounds were finally tested for their in vivo efficacy in SCID type mice HCT-116 tumor model. Results: The screening results revealed that compounds 4c, 4f, 4i and 4j showed promising activity in in vitro study. However, compound 4c was found to be the most potent candidate with 23% tumor growth inhibition in HCT-116 tumor mice model. Conclusion: The structure activity relationship suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2 c]quinolone moiety seems to have an important position for cytotoxicity activity. However, 3- chloro substitution at C4 aryl ring showed a significant alteration of the bioactive conformer of the parent scaffold and outcome with compound 4c as the most potent candidate of the series.

Virtual Screening, Molecular docking and in-silico ADME-Tox analysis for identification of potential main protease (Mpro) enzyme inhibitors

2020 ◽  
Vol 18 ◽  
Author(s):  
Debadash Panigrahi ◽  
Ganesh Prasad Mishra
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
In Silico ◽  
Data Bank ◽  
Future Research ◽  
Reference Compound ◽  
Unexpected Death ◽  
Main Protease ◽  
In Silico Admet

Objective:: Recent pandemic caused by SARS-CoV-2 described in Wuhan China in December-2019 spread widely almost all the countries of the world. Corona virus (COVID-19) is causing the unexpected death of many peoples and severe economic loss in several countries. Virtual screening based on molecular docking, drug-likeness prediction, and in silico ADMET study has become an effective tool for the identification of small molecules as novel antiviral drugs to treat diseases. Methods:: In the current study, virtual screening was performed through molecular docking for identifying potent inhibitors against Mpro enzyme from the ZINC library for the possible treatment of COVID-19 pandemic. Interestingly, some compounds are identified as possible anti-covid-19 agents for future research. 350 compounds were screened based on their similarity score with reference compound X77 from ZINC data bank and were subjected to docking with crystal structure available of Mpro enzyme. These compounds were then filtered by their in silico ADME-Tox and drug-likeness prediction values. Result:: Out of these 350 screened compounds, 10 compounds were selected based on their docking score and best docked pose in comparison to the reference compound X77. In silico ADME-Tox and drug likeliness predictions of the top compounds were performed and found to be excellent results. All the 10 screened compounds showed significant binding pose with the target enzyme main protease (Mpro) enzyme and satisfactory pharmacokinetic and toxicological properties. Conclusion:: Based on results we can suggest that the identified compounds may be considered for therapeutic development against the COVID-19 virus and can be further evaluated for in vitro activity, preclinical, clinical studies and formulated in a suitable dosage form to maximize their bioavailability.

scholarly journals In vitro cytotoxicity of Aspilia pluriseta Schweinf. extract fractions

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sospeter N. Njeru ◽  
Jackson M. Muema
Keyword(s):  
Biological Activities ◽  
Vero Cells ◽  
In Vitro Cytotoxicity ◽  
Root Extract ◽  
Lack Of Information ◽  
Information Gap ◽  
Diphenyltetrazolium Bromide ◽  
Potential Use

Abstract Objectives We and others have shown that Aspilia pluriseta is associated with various biological activities. However, there is a lack of information on its cytotoxicity. This has created an information gap about the safety of A. pluriseta extracts. As an extension to our recent publication on the antimicrobial activity and the phytochemical characterization of A. pluriseta root extracts, here we report on cytotoxicity of tested solvent fractions. We evaluated the potential cytotoxicity of these root extract fractions on Vero cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results We show that all solvent extract fractions (except methanolic solvent fractions) had cytotoxic concentration values that killed 50% of the Vero cells (CC50) greater than 20 µg/mL and selectivity index (SI) greater than 1.0. Taken together, we demonstrate that, A. pluriseta extract fractions’ earlier reported bioactivities are within the acceptable cytotoxicity and selective index limits. This finding scientifically validates the potential use of A. pluriseta in the discovery of safe therapeutics agents.

Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods

2021 ◽  
Vol 18 ◽  
Author(s):  
Jelena Bošković ◽  
Dušan Ružić ◽  
Olivera Čudina ◽  
Katarina Nikolic ◽  
Vladimir Dobričić
Keyword(s):  
Molecular Docking ◽  
External Validation ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Qsar Analysis ◽  
In Silico Admet ◽  
Cox 2 ◽  
Lox Inhibitors

Background: Inflammation is common pathogenesis of many diseases progression, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of the synthesis of inflammatory mediators by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides a challenging strategy for the development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5-LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, was clustered as potential dual COX-2 and 5-LOX inhibitors with iron-chelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g, and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had an ADMET_Risk score less than 7 and a CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors, and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g, and 1l) are selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.

In silico specificity determination of neoantigen-reactive T-lymphocytes

2021 ◽  
Vol 67 (3) ◽  
pp. 251-258
Author(s):  
A.E. Kniga ◽  
I.V. Polyakov ◽  
A.V. Nemukhin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Structural Features ◽  
Immune Recognition ◽  
Protein Protein Interactions ◽  
Binary Classifiers

Effective personalized immunotherapies of the future will need to capture not only the peculiarities of the patient’s tumor but also of his immune response to it. In this study, using results of in vitro high-throughput specificity assays, and combining comparative models of pMHCs and TCRs using molecular docking, we have constructed all-atom models for the putative complexes of all their possible pairwise TCR-pMHC combinations. For the models obtained we have calculated a dataset of physics-based scores and have trained binary classifiers that perform better compared to their solely sequence-based counterparts. These structure-based classifiers pinpoint the most prominent energetic terms and structural features characterizing the type of protein-protein interactions that underlies the immune recognition of tumors by T cells.

Sign in / Sign up

Export Citation Format

Share Document