Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Molecular Docking Evaluation of (E)-5-arylidene-2-thioxothiazolidin-4-one Derivatives as Selective Bacterial Adenylate Kinase Inhibitors.

ABSTRACT: Multi-drug resistant microorganism infections with emerging problems that require not only a prevention strategy, but also the development of new inhibitory compounds. Six previously synthesized 5-arylidene-2-thioxothiazolidin-4-one derivatives 1a?f, were screened for inhibitory activity on adenylate kinases of different origins by molecular docking. The compounds 1c and 1d were the most efficient inhibitors of bacterial and some archean adenylate kinases. Hydrogen bond interactions were observed with the residues belonging to the ATP binding site. Moreover human adenylate kinases are poor targets, suggesting that this selectivity offers promising prospectives for refining the structure of our compounds.

SUBMITTER: Ionescu MI

PROVIDER: S-EPMC6102543 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Molecular Docking Evaluation of (E)-5-arylidene-2-thioxothiazolidin-4-one Derivatives as Selective Bacterial Adenylate Kinase Inhibitors.

Ionescu Mihaela Ileana MI Oniga Ovidiu O

Molecules (Basel, Switzerland) 20180503 5

Multi-drug resistant microorganism infections with emerging problems that require not only a prevention strategy, but also the development of new inhibitory compounds. Six previously synthesized 5-arylidene-2-thioxothiazolidin-4-one derivatives 1a⁻f, were screened for inhibitory activity on adenylate kinases of different origins by molecular docking. The compounds 1c and 1d were the most efficient inhibitors of bacterial and some archean adenylate kinases. Hydrogen bo ...[more]

PMID: 29751552

Similar Datasets

Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors.

Project description:Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. S1, S2 and S3 exhibited good cytotoxic activity on both cell lines with an IC50 range of 6.42 - 20.20 μM. In general, substitution of a five-membered heterocyclic ring containing NO2, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, S1, was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity.

| S-EPMC5772076 | biostudies-literature

2-Arylidene Hydrazinecarbodithioates as Potent, Selective Inhibitors of Cystathionine ?-Lyase (CSE).

Project description:Hydrogen sulfide is produced from l-cysteine by the action of both cystathionine ?-lyase (CSE) and cystathionine ?-synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis, hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotransmitter play a role. We describe the discovery and development of a novel series of potent CSE inhibitors that show increased activity over the benchmark inhibitor and, importantly, display high selectivity for CSE versus CBS.

| S-EPMC5733271 | biostudies-literature

Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A.

Project description:Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/β). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC50 0.028 μM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC50 0.033 μM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved.

| S-EPMC8623179 | biostudies-literature

Docking-Based 3D-QSAR Studies for 1,3,4-oxadiazol-2-one Derivatives as FAAH Inhibitors.

Project description:This work aimed to construct 3D-QSAR CoMFA and CoMSIA models for a series of 31 FAAH inhibitors, containing the 1,3,4-oxadiazol-2-one moiety. The obtained models were characterized by good statistical parameters: CoMFA Q2 = 0.61, R2 = 0.98; CoMSIA Q2 = 0.64, R2 = 0.93. The CoMFA model field contributions were 54.1% and 45.9% for steric and electrostatic fields, respectively. In the CoMSIA model, electrostatic, steric, hydrogen bond donor, and hydrogen acceptor properties were equal to 34.6%, 23.9%, 23.4%, and 18.0%, respectively. These models were validated by applying the leave-one-out technique, the seven-element test set (CoMFA r2test-set = 0.91; CoMSIA r2test-set = 0.91), a progressive scrambling test, and external validation criteria developed by Golbraikh and Tropsha (CoMFA r20 = 0.98, k = 0.95; CoMSIA r20 = 0.98, k = 0.89). As the statistical significance of the obtained model was confirmed, the results of the CoMFA and CoMSIA field calculation were mapped onto the enzyme binding site. It gave us the opportunity to discuss the structure-activity relationship based on the ligand-enzyme interactions. In particular, examination of the electrostatic properties of the established CoMFA model revealed fields that correspond to the regions where electropositive substituents are not desired, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one moiety. This highlights the importance of heterocycle, a highly electronegative moiety in this area of each ligand. Examination of hydrogen bond donor and acceptor properties contour maps revealed several spots where the implementation of another hydrogen-bond-donating moiety will positively impact molecules' binding affinity, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one ring. On the other hand, there is a large isopleth that refers to the favorable H-bond properties close to the terminal phenoxy group of a ligand, which means that, generally speaking, H-bond acceptors are desired in this area.

| S-EPMC8201265 | biostudies-literature

Molecular docking and fluorescence characterization of benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives, a novel class of selective cyclooxygenase-2 inhibitors.

Project description:The aims of this study were: (i) to explore the structure-activity relationship of some new anti-inflammatory benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives 1-11; and (ii) to evaluate the possibility of using the most active compounds as fluorescent probes to determine tumours or their progression. Therefore, to know the precise mechanism by which these compounds interact with cyclooxygenase (COX)-2 enzyme, a molecular docking study was carried out; to assess spectroscopic characteristics, their absorption and emission properties were determined. The results demonstrated that some derivatives of benzothieno[3,2-d] pyrimidine exhibit interesting anti-inflammatory properties related to interactions with active sites of COX-2 and are fluorescent. The antipyrine-bearing compound 4 displayed high COX-2 affinity (ΔG = -9.4) and good fluorescent properties (Φfl = 0.032). Thus, some members of this new class of anti-inflammatory may be promising for fluorescence imaging of cancer cells that express the COX-2 enzyme. Further in vitro and in vivo studies are needed to confirm this hypothesis.

| S-EPMC6271841 | biostudies-literature

Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors.

Project description:The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 ?M), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 ?M inhibited only Limk1 and STK16 with ?80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

| S-EPMC4349585 | biostudies-literature

Molecular docking of 1H-pyrazole derivatives to receptor tyrosine kinase and protein kinase for screening potential inhibitors.

Project description:Tyrosine kinase receptor and protein kinases drawn much attention for the scientific fraternity in drug discovery due to its important role in different cancer, cardiovascular diseases and other hyper-proliferative disorders. Docking studies of pyrazole derivatives with tyrosine kinase and different serine/threonine protein kinases were employed by using flexible ligand docking approach of AutoDock 4.2. Among the molecules tested for docking study, 2-(4-chlorophenyl)-5-(3-(4-chlorophenyl)-5-methyl-1- phenyl-1H-pyrazol-4-yl)-1,3,4-thiadiazole (1b), 2-(4-methoxyphenyl)-5-(3-(4-methoxyphenyl)-5-methyl-1-phenyl-1H-pyrazol-4-yl)- 1,3,4-thiadiazole (1d) and 2-(4-chlorophenyl)-5-(3-(4-chlorophenyl)-5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,3,4-thiadiazole (2b) revealed minimum binding energy of -10.09, -8.57 and -10.35 kJ/mol with VEGFR-2 (2QU5), Aurora A (2W1G) and CDK2 (2VTO) protein targets, respectively. These proteins are representatives of plausible models of interactions with different anticancer agents. All the ligands were docked deeply within the binding pocket region of all the three proteins, showing reasonable hydrogen bonds. The docking study results showed that these pyrazole derivatives are potential inhibitor of all the three protein targets; and also all these docked compounds have good inhibition constant, vdW + Hbond + desolv energy with best RMSD value.

| S-EPMC4135288 | biostudies-literature

Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors.

Project description:Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC50?=?348?nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL.

| S-EPMC6009861 | biostudies-literature

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.

Project description:A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 Å. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.

| S-EPMC4394340 | biostudies-literature

Novel Anti-Melanogenic Compounds, (Z)-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights.

Project description:To confirm that the β-phenyl-α,β-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve (Z)-5-(substituted benzylidene)-4-thioxothiazolidin-2-one ((Z)-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound 2b (IC50 = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies' results confirmed that compounds 2b and 2f are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that 2b and 2f might potently inhibit human tyrosinase. In vitro assays of 2b and 2f were conducted using B16F10 melanoma cells. Compounds 2b and 2f significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of 2b at 10 µM and 2f at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds 2b and 2f similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.

| S-EPMC8400311 | biostudies-literature