Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation.

ABSTRACT: A series of oxime ethers with C?-C? fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel-Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 ?M, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro.

SUBMITTER: Tan J

PROVIDER: S-EPMC6017342 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation.

Tan Jie J Zhou Min M Cui Xinhua X Wei Zhuocai Z Wei Wanxing W

Molecules (Basel, Switzerland) 20180312 3

A series of oxime ethers with C₆-C₄ fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel-Crafts reaction, esterification (or amidation), and oximation from <i>p</i>-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cell ...[more]

PMID: 29534537

Similar Datasets

Eco-friendly synthesis, physicochemical studies, biological assay and molecular docking of steroidal oxime-ethers.

Project description:The aim of this study was to report the synthesis of biologically active compounds; 7-(2'-aminoethoxyimino)-cholest-5-ene (4), a steroidal oxime-ether and its derivatives (5, 6) via a facile microwave assisted solvent free reaction methodology. This new synthetic, eco-friendly, sustainable protocol resulted in a remarkable improvement in the synthetic efficiency (85-93 % yield) and high purity using basic alumina. The synthesized compounds were screened for their antibacterial against six bacterial strains by disc diffusion method and antioxidant potential by DPPH assay. The binding capabilities of a compound 6 exhibiting good antibacterial potential were assessed on the basis of molecular docking studies and four types of three-dimensional molecular field descriptors. Moreover the structure-antimicrobial activity relationships were studied using some physicochemical and quantum-chemical parameters with GAMESS interface as well as WebMO Job Manager by using the basic level of theory. Hence, this synthetic approach is believed to provide a better scope for the synthesis of steroidal oxime-ether analogues and will be a more practical alternative to the presently existing procedures. Moreover, detailed in silico docking studies suggested the plausible mechanism of steroidal oxime-ethers as effective antimicrobial agents.

| S-EPMC4908662 | biostudies-literature

Discovery of YopE Inhibitors by Pharmacophore-Based Virtual Screening and Docking.

Project description:Gram-negative bacteria Yersinia secrete virulence factors that invade eukaryotic cells via type III secretion system. One particular virulence member, Yersinia outer protein E (YopE), targets Rho family of small GTPases by mimicking regulator GAP protein activity, and its secretion mainly induces cytoskeletal disruption and depolymerization of actin stress fibers within the host cell. In this work, potent drug-like inhibitors of YopE are investigated with virtual screening approaches. More than 500,000 unique small molecules from ZINC database were screened with a five-point pharmacophore, comprising three hydrogen acceptors, one hydrogen donor, and one ring, and derived from different salicylidene acylhydrazides. Binding modes and features of these molecules were investigated with a multistep molecular docking approach using Glide software. Virtual screening hits were further analyzed based on their docking score, chemical similarity, pharmacokinetic properties, and the key Arg144 interaction along with other active site residue interactions with the receptor. As a final outcome, a diverse set of ligands with inhibitory potential were proposed.

| S-EPMC4393062 | biostudies-literature

Novel Class of Chalcone Oxime Ethers as Potent Monoamine Oxidase-B and Acetylcholinesterase Inhibitors.

Project description:Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except COE-17 and COE-24, had potent and/or significant selective inhibitory effects on MAO-B. COE-6 potently inhibited MAO-B with an IC50 value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. COE-7, and COE-22 were also active against MAO-B, both had an IC50 value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. COE-13 most potently inhibited MAO-A (IC50 = 0.88 µM) and also significantly inhibited MAO-B (IC50 = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. COE-19 and COE-22 inhibited AChE with IC50 values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of COE-22 for MAO-B was higher than that of COE-6 (SI = 778.6 vs. 222.2), but the IC50 value (0.028 µM) was slightly lower than that of COE-6 (0.018 µM). In reversibility experiments, inhibitions of MAO-B by COE-6 and COE-22 were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with Ki values of 0.0075 and 0.010 µM, respectively. Our results show that COE-6 and COE-22 are potent, selective MAO-B inhibitors, and COE-22 is a candidate of dual-targeting molecule for MAO-B and AChE.

| S-EPMC7288026 | biostudies-literature

Pharmacophore modeling, virtual screening, and molecular docking studies for discovery of novel Akt2 inhibitors.

Project description:Akt2 is considered as a potential target for cancer therapy. In order to find novel Akt2 inhibitors which have different scaffolds, structure-based pharmacophore model and 3D-QSAR pharmacophore model were built and validated by different methods. Then, they were used for chemical databases virtual screening. The selected compounds were further analyzed and refined using drug-like filters and ADMET analysis. Finally, seven hits with different scaffolds were picked out for docking studies. These seven hits were predicted to have high inhibitory activity and good ADMET properties, they may act as novel leads for Akt2 inhibitors designing.

| S-EPMC3558715 | biostudies-literature

3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors.

Project description:p-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only the useful molecular target in treating life-threatening tyrosinemia type I, but also an important target for chemical herbicides. A combined in silico structure-based pharmacophore and molecular docking-based virtual screening were performed to identify novel potential HPPD inhibitors. The complex-based pharmacophore model (CBP) with 0.721 of ROC used for screening compounds showed remarkable ability to retrieve known active ligands from among decoy molecules. The ChemDiv database was screened using CBP-Hypo2 as a 3D query, and the best-fit hits subjected to molecular docking with two methods of LibDock and CDOCKER in Accelrys Discovery Studio 2.5 (DS 2.5) to discern interactions with key residues at the active site of HPPD. Four compounds with top rankings in the HipHop model and well-known binding model were finally chosen as lead compounds with potential inhibitory effects on the active site of target. The results provided powerful insight into the development of novel HPPD inhibitors herbicides using computational techniques.

| S-EPMC6152767 | biostudies-literature

Lead Discovery of SARS-CoV-2 Main Protease Inhibitors through Covalent Docking-Based Virtual Screening.

Project description:During almost all 2020, coronavirus disease 2019 (COVID-19) pandemic has constituted the major risk for the worldwide health and economy, propelling unprecedented efforts to discover drugs for its prevention and cure. At the end of the year, these efforts have culminated with the approval of vaccines by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) giving new hope for the future. On the other hand, clinical data underscore the urgent need for effective drugs to treat COVID-19 patients. In this work, we embarked on a virtual screening campaign against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro chymotrypsin-like cysteine protease employing our in-house database of peptide and non-peptide ligands characterized by different types of warheads acting as Michael acceptors. To this end, we employed the AutoDock4 docking software customized to predict the formation of a covalent adduct with the target protein. In vitro verification of the inhibition properties of the most promising candidates allowed us to identify two new lead inhibitors that will deserve further optimization. From the computational point of view, this work demonstrates the predictive power of AutoDock4 and suggests its application for the in silico screening of large chemical libraries of potential covalent binders against the SARS-CoV-2 Mpro enzyme.

| S-EPMC8029447 | biostudies-literature

Discovery of VEGFR2 inhibitors by integrating naive Bayesian classification, molecular docking and drug screening approaches.

Project description:The high morbidity and mortality of cancer make it one of the leading causes of global death, thus it is an urgent need to develop effective drugs for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR2) acts as a central modulator of angiogenesis, and is therefore an important pharmaceutical target for developing anti-angiogenic agents. In this study, ligand-based naïve Bayesian (NB) models and structure-based molecular docking were combined to develop a virtual screening (VS) pipeline for identifying potential VEGFR2 inhibitors from FDA-approved drugs. The best validated naïve Bayesian model (NB-c) gave Matthews correlation coefficients of 0.966 and 0.951 for the test set and external validation set, respectively. 1841 FDA-approved drugs were sequentially screened by the optimal model NB-c and molecular docking module LibDock. By analyzing the results of VS, 9 top ranked drugs with EstPGood value ≥ 0.6 and LibDock Score ≥ 120 were chosen for biological validation. VEGFR2 kinase assay results demonstrated that flubendazole, rilpivirine and papaverine showed VEGFR2 inhibitory activities with IC50 values ranging from 0.47 to 6.29 μM. Binding mode analysis with CDOCKER revealed the action mechanism of the 3 hit drugs binding to VEGFR2. In summary, we not only proposed an integrated VS pipeline for potential VEGFR2 inhibitors screening, but also identified 3 FDA-approved drugs as novel VEGFR2 inhibitors, which could be used to design and develop new antiangiogenic agents.

| S-EPMC9078101 | biostudies-literature

Reaction discovery using microfluidic-based multidimensional screening of polycyclic iminium ethers.

Project description:Polycyclic iminium ethers are ambident electrophilic intermediates that react with a range of nucleophiles in a highly condition-dependent manner to afford densely functionalized lactams. In an effort to expand the scope of reactivity and assist in the generation of new chemotypes from these intermediates, several iminium ethers were subjected to reaction screening using an automated microfluidics reaction platform. Application of this approach led to the discovery of several interesting reaction pathways involving the iminium ether intermediates that will be described.

| S-EPMC2846649 | biostudies-literature

The discovery of novel HDAC3 inhibitors via virtual screening and in vitro bioassay.

Project description:Histone deacetylase 3 (HDAC3) is a potential target for the treatment of human diseases such as cancers, diabetes, chronic inflammation and neurodegenerative diseases. Previously, we proposed a virtual screening (VS) pipeline named "Hypo1_FRED_SAHA-3" for the discovery of HDAC3 inhibitors (HDAC3Is) and had thoroughly validated it by theoretical calculations. In this study, we attempted to explore its practical utility in a large-scale VS campaign. To this end, we used the VS pipeline to hierarchically screen the Specs chemical library. In order to facilitate compound cherry-picking, we then developed a knowledge-based pose filter (PF) by using our in-house quantitative structure activity relationship- (QSAR-) modelling approach and coupled it with FRED and Autodock Vina. Afterward, we purchased and tested 11 diverse compounds for their HDAC3 inhibitory activity in vitro. The bioassay has identified compound 2 (Specs ID: AN-979/41971160) as a HDAC3I (IC50 = 6.1 μM), which proved the efficacy of our workflow. As a medicinal chemistry study, we performed a follow-up substructure search and identified two more hit compounds of the same chemical type, i.e. 2-1 (AQ-390/42122119, IC50 = 1.3 μM) and 2-2 (AN-329/43450111, IC50 = 12.5 μM). Based on the chemical structures and activities, we have demonstrated the essential role of the capping group in maintaining the activity for this class of HDAC3Is. In addition, we tested the hit compounds for their in vitro activities on other HDACs, including HDAC1, HDAC2, HDAC8, HDAC4 and HDAC6. We have identified these compounds are HDAC1/2/3 selective inhibitors, of which compound 2 show the best selectivity profile. Taken together, the present study is an experimental validation and an update to our earlier VS strategy. The identified hits could be used as starting structures for the development of highly potent and selective HDAC3Is.

| S-EPMC5978667 | biostudies-literature

Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies.

Project description:Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC50 values of less than 10 nM and 10 ?M. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages.

| S-EPMC7397142 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data