Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of benzothiazolylquinoline conjugates as novel human A3 receptor antagonists: biological evaluations and molecular docking studies.

ABSTRACT: Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A3 receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the hA3 receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compounds are rationalized with the molecular docking results. Compound 6a showed best potency and selectivity at hA3 among other adenosine receptors.

SUBMITTER: Sarkar B

PROVIDER: S-EPMC5830763 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery of benzothiazolylquinoline conjugates as novel human A3 receptor antagonists: biological evaluations and molecular docking studies.

Sarkar Bidisha B Maiti Santanu S Jadhav Gajanan Raosaheb GR Paira Priyankar P

Royal Society open science 20180207 2

Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A3 receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the hA3 receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compou ...[more]

PMID: 29515874

Similar Datasets

Novel N-substituted indole hydrazones as potential antiplatelet agents: synthesis, biological evaluations, and molecular docking studies.

Project description:Background and purpose:Antiplatelet agents can diminish the chance of coronary heart diseases due to the prevention of unusual clotting in the arteries by inhibiting platelet aggregation and avoiding the formation of a blood clot. This mechanism can help to prevent ischemic stroke likewise. To improve the activity of these drugs and reduce their side effects, further studies are required. Experimental approach:Based on the previous studies representing the promising antiplatelet activity of indole hydrazones, a series of their homologs containing twenty-one compounds were prepared in two steps. First, alkylation reaction on the nitrogen of the indole ring, and second, chiff base formation by condensation of a primary amine and N-substituted indole-3 carbaldehyde. Consequently, their platelet anti-aggregation activity was evaluated based on the Born turbidimetric method. Findings/Results:Most of the compounds exhibited noticeable activity against platelet aggregation induced by arachidonic acid. Amongst them, two compounds 2e and 2f showed higher activity with IC50 values that made comparable to indomethacin and acetylsalicylic acid as standard drugs and had no toxicity on platelets. Conclusion and implications:The synthesized compounds exhibited promising activity against arachidonic acid-induced aggregation; however, none of them showed noticeable antiplatelet activity induced by adenosine di-phosphate. Chemical structure comparison of the prepared derivatives indicated the existence of a lipophilic medium-sized group on the phenyl ring increased their activity. In addition, the docking studies confirmed this hydrophobic interaction in the lipophilic pocket of cyclooxygenase-1 enzyme suggesting that hydrophobicity of this region plays a pivotal role in the anti-platelet activity of these compounds. To prove this finding, the enzymatic evaluation with the target enzyme is required.

| S-EPMC8621843 | biostudies-literature

Synthesis, pharmacological evaluations, and molecular docking studies on a new 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework: Rigidification of D1 receptor selective 1-phenylbenzazepines and discovery of a new 5-HT6 receptor scaffold.

Project description:The novel 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework, a structurally rigidified variant of the 1-phenylbenzazepine template, was synthesized via direct arylation as a key reaction. Evaluation of the binding affinities of the rigidified compounds across a battery of serotonin, dopamine, and adrenergic receptors indicates that this scaffold unexpectedly has minimal affinity for D1 and other dopamine receptors and is selective for the 5-HT6 receptor. The affinity of these systems at the 5-HT6 receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D1 receptor affinity of the rigidified compounds may be due in part to weaker H-bonding interactions between the oxygenated moieties on the compounds and specific receptor residues. Key receptor-ligand H-bonding interactions, salt bridges, and π-π interactions appear to be responsible for the 5-HT6 receptor affinity of the compounds. Compounds 10 (6,7-dimethoxy-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) and 12 (6,7-dimethoxy-2-methyl-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) have been identified as structurally novel, high affinity (Ki = 5 nM), selective 5-HT6 receptor ligands.

| S-EPMC7442682 | biostudies-literature

The Conjugates of Indolo[2,3-b]quinoline as Anti-Pancreatic Cancer Agents: Design, Synthesis, Molecular Docking and Biological Evaluations.

Project description:New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5H-indolo[2,3-b]quinoline (2), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC50 values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate 2 did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA-topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II-DNA complex compared to DiMIQ. Conjugate 2 was predicted to have the strongest binding to the enzyme-DNA complex, with a Ki value of 2.8 nM.

| S-EPMC10932360 | biostudies-literature

Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking.

Project description:Treatment of hyperthyroidism, a common clinical condition that can have serious manifestations in the elderly, has remained essentially unchanged for >30 years. Directly antagonizing the effect of the thyroid hormone at the receptor level may be a significant improvement for the treatment of hyperthyroid patients. We built a computer model of the thyroid hormone receptor (TR) ligand-binding domain in its predicted antagonist-bound conformation and used a virtual screening algorithm to select 100 TR antagonist candidates out of a library of >250,000 compounds. We were able to obtain 75 of the compounds selected in silico and studied their ability to act as antagonists by using cultured cells that express TR. Fourteen of these compounds were found to antagonize the effect of T3 on TR with IC50s ranging from 1.5 to 30 microM. A small virtual library of compounds, derived from the highest affinity antagonist (1-850) that could be rapidly synthesized, was generated. A second round of virtual screening identified new compounds with predicted increased antagonist activity. These second generation compounds were synthesized, and their ability to act as TR antagonists was confirmed by transfection and receptor binding experiments. The extreme structural diversity of the antagonist compounds shows how receptor-based virtual screening can identify diverse chemistries that comply with the structural rules of TR antagonism.

| S-EPMC165879 | biostudies-literature

Discovery of novel dual adenosine A1/A2A receptor antagonists using deep learning, pharmacophore modeling and molecular docking.

Project description:Adenosine receptors (ARs) have been demonstrated to be potential therapeutic targets against Parkinson's disease (PD). In the present study, we describe a multistage virtual screening approach that identifies dual adenosine A1 and A2A receptor antagonists using deep learning, pharmacophore models, and molecular docking methods. Nineteen hits from the ChemDiv library containing 1,178,506 compounds were selected and further tested by in vitro assays (cAMP functional assay and radioligand binding assay); of these hits, two compounds (C8 and C9) with 1,2,4-triazole scaffolds possessing the most potent binding affinity and antagonistic activity for A1/A2A ARs at the nanomolar level (pKi of 7.16-7.49 and pIC50 of 6.31-6.78) were identified. Further molecular dynamics (MD) simulations suggested similarly strong binding interactions of the complexes between the A1/A2A ARs and two compounds (C8 and C9). Notably, the 1,2,4-triazole derivatives (compounds C8 and C9) were identified as the most potent dual A1/A2A AR antagonists in our study and could serve as a basis for further development. The effective multistage screening approach developed in this study can be utilized to identify potent ligands for other drug targets.

| S-EPMC7978378 | biostudies-literature

Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A3 receptor antagonists: SAR and molecular modeling studies.

Project description:A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives (6a-6l) showed weak to moderate affinity towards the human adenosine receptors. Further modification to 2-aminoimidazolyl-thiazole derivatives (12a-12l) resulted in an improvement of affinity at adenosine A1, A2A and A3 receptor subtypes. Compound 12b was the most potent and selective non-xanthine human adenosine A3 receptor antagonist of this series. A receptor-based modeling study was performed to explore the possible binding mode of these novel 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives into human adenosine A1, A2A and A3 receptor subtypes.

| S-EPMC6072342 | biostudies-literature

Design, Synthesis, and Biological Activity Studies of Istradefylline Derivatives Based on Adenine as A2A Receptor Antagonists.

Project description:Due to its double bond, istradefylline rapidly isomerizes to Z-istradefylline when exposed to normal daylight in dilute solution. To solve the poor photostability of the istradefylline solution, a series of istradefylline derivatives (in total 17 compounds, including II-1 and II-2 series) were designed and synthesized, and their biological activity in inhibiting cAMP was evaluated. The IC50 values of compounds II-1-3, II-2-1, II-2-2, II-2-3, II-2-4, and II-2-6 were 7.71, 6.52, 6.16, 7.23, 7.96, and 9.68 μg/mL, respectively, which had the same order of activity as that of istradefylline (IC50 value was 1.94 μg/mL). The preliminary structure-activity relationship suggested that the 6-amino in adenine played an important role in binding an A2A receptor. The results of photostability experiments showed that the photostability of the target compounds of II-1 and II-2 series was improved when compared with that of istradefylline.

| S-EPMC7906590 | biostudies-literature

Discovery of Novel Glucagon Receptor Antagonists Using Combined Pharmacophore Modeling and Docking.

Project description:Glucagon and the glucagon receptor are most important molecules control over blood glucose concentrations. These two molecules are very important to studies of type 2 diabetic patients. In literature, several classes of small molecule antagonists of the human glucagon receptor have been reported. Glucagon receptor antagonist could decrease hepatic glucose output and improve glucose control in diabetic patients. In this research, to identify novel and diverse leads for use in potent glucagon receptor antagonist design, a ligand-based pharmacophore modeling, was developed using the best conformations of training set compounds. The best five features pharmacophore model, called Hypo1, includes, hydrogen bond acceptors, two hydrophobic, and positive ionizable features, which has the highest correlation coefficient (0.805), cost difference (64.38), low RMS (2.148), as well as it shows a high goodness of fit and enrichment factor. The generated pharmacophore model has been validated by using a series of similar structures with varying affinities for the glucagon receptor. Then, the developed model has been applied as a search query in different database searching with the main objective of finding novel molecules which have the potential to be be modified into novel lead compounds. As a result, some hit molecules were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. The results from pharmacophore modeling and molecular docking are complementary to each other and could serve as a useful way for the discovery of potent small molecules as glucagon receptor antagonist.

| S-EPMC6269551 | biostudies-literature

Studies of new fused benzazepine as selective dopamine D3 receptor antagonists using 3D-QSAR, molecular docking and molecular dynamics.

Project description:In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q(2) = 0.603, R(2) (ncv) = 0.829, R(2) (pre) = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q(2) = 0.506, R(2) (ncv) =0.838, R(2) (pre) = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R(3) substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R(1) substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists.

| S-EPMC3083700 | biostudies-literature

Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives.

Project description:A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the "tail approach" and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.

| S-EPMC8196973 | biostudies-literature