scholarly journals Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-Inflammatory Effects Through SHIP1/STAT3 Complexes

2020 ◽  
Author(s):  
Thomas C. Chamberlain ◽  
Sylvia T. Cheung ◽  
Jeff S.J. Yoon ◽  
Andrew Ming-Lum ◽  
Bernd R. Gardill ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Interleukin 10 ◽  
Docking Studies ◽  
Mechanisms Of Action ◽  
Drug Binding ◽  
Inositol Polyphosphate ◽  
Anti Inflammatory ◽  
Allosteric Regulators ◽  
Inflammatory Action ◽  
Pro Inflammatory Cytokines

ABSTRACTThe anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells, and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1, and provide a rationale for use of allosteric SHIP1-activating compounds which mimic the beneficial anti-inflammatory actions of IL10.

scholarly journals Long-Lasting Anti-Inflammatory and Antinociceptive Effects of Acute Ammonium Glycyrrhizinate Administration: Pharmacological, Biochemical, and Docking Studies

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2453 ◽  
Author(s):  
Francesco Maione ◽  
Paola Minosi ◽  
Amalia Di Giannuario ◽  
Federica Raucci ◽  
Maria Giovanna Chini ◽  
...  
Keyword(s):  
Animal Models ◽  
Antinociceptive Effect ◽  
Binding Pocket ◽  
Docking Studies ◽  
Prostaglandin E ◽  
Single Administration ◽  
Antinociceptive Effects ◽  
Anti Inflammatory

The object of the study was to estimate the long-lasting effects induced by ammonium glycyrrhizinate (AG) after a single administration in mice using animal models of pain and inflammation together with biochemical and docking studies. A single intraperitoneal injection of AG was able to produce anti-inflammatory effects in zymosan-induced paw edema and peritonitis. Moreover, in several animal models of pain, such as the writhing test, the formalin test, and hyperalgesia induced by zymosan, AG administered 24 h before the tests was able to induce a strong antinociceptive effect. Molecular docking studies revealed that AG possesses higher affinity for microsomal prostaglandin E synthase type-2 compared to type-1, whereas it seems to locate better in the binding pocket of cyclooxygenase (COX)-2 compared to COX-1. These results demonstrated that AG induced anti-inflammatory and antinociceptive effects until 24–48 h after a single administration thanks to its ability to bind the COX/mPGEs pathway. Taken together, all these findings highlight the potential use of AG for clinical treatment of pain and/or inflammatory-related diseases.

scholarly journals Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes

iScience ◽  
2020 ◽  
Vol 23 (8) ◽  
pp. 101433
Author(s):  
Thomas C. Chamberlain ◽  
Sylvia T. Cheung ◽  
Jeff S.J. Yoon ◽  
Andrew Ming-Lum ◽  
Bernd R. Gardill ◽  
...  
Keyword(s):  
Small Molecule ◽  
Interleukin 10 ◽  
Anti Inflammatory ◽  
Allosteric Regulators

Molecular Docking Studies of Enzyme Binding Drugs on Family of Cytochrome P450

2020 ◽  
Vol 12 (1) ◽  
pp. 83-87
Author(s):  
Rolly Yadav ◽  
Anwesh Pandey ◽  
Nidhi Awasthi ◽  
Anamika Shukla
Keyword(s):  
Molecular Docking ◽  
Binding Pocket ◽  
Docking Studies ◽  
Drug Binding ◽  
Binding Modes ◽  
Computational Docking ◽  
Molecular Events ◽  
Modern Drug ◽  
Autodock 4.0 ◽  
Almost All

The combination of experimental and computational strategies has been of great value in the identification and development of metabolism of drugs. Nowadays modern drug design, molecular docking methods are helpful in exploring the ligand conformations adopted within the binding sites of macro-molecular targets such as DNA, proteins, and enzymes, there by reducing cost, time and wayward efforts of chemist. Since the development of the algorithms in the 1980s, molecular docking became an important tool in drug discovery like investigation of crucial molecular events, including ligand binding modes and the corresponding intermolecular interactions that stabilize the ligand-receptor complex, can be conveniently performed. In present study we have tried to investigate the drug binding pocket of various cytochrome (CYP) enzymes found in humans. All structures of drugs are optimized at B3LYP/6-31** level of theory using Gaussian program suite. Docking of substrate-enzyme duo was done using AUTODOCK 4.0. Computational docking revealed that almost all drugs have same binding pocket with varied binding affinities due to change in interactions and interacting distance from heme prosthetic moiety with transition metal iron as chelating ion.

scholarly journals ATP-Binding Pocket-Targeted Suppression of Src and Syk by Luteolin Contributes to Its Anti-Inflammatory Action

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jeong-Oog Lee ◽  
Deok Jeong ◽  
Mi-Yeon Kim ◽  
Jae Youl Cho
Keyword(s):  
Nuclear Translocation ◽  
Binding Pocket ◽  
Luciferase Reporter ◽  
Prostaglandin E ◽  
Atp Binding ◽  
Luciferase Reporter Gene ◽  
Gene Assay ◽  
Anti Inflammatory ◽  
Inflammatory Action ◽  
Artemisia Asiatica

Luteolin is a flavonoid identifiedas a major anti-inflammatory componentofArtemisia asiatica. Numerous reports have demonstrated the ability of luteolin to suppress inflammation in a variety of inflammatory conditions. However, its exact anti-inflammatory mechanism has not been fully elucidated. In the present study, the anti-inflammatory mode of action in activated macrophages of luteolin fromArtemisia asiaticawas examined by employing immunoblotting analysis, a luciferase reporter gene assay, enzyme assays, and an overexpression strategy. Luteolin dose-dependently inhibited the secretion of nitric oxide (NO) and prostaglandin E2(PGE2) and diminished the levels of mRNA transcripts of inducible NO synthase (iNOS), tumor necrosis factor- (TNF-)α, and cyclooxygenase-2 (COX-2) in lipopolysaccharide- (LPS-) and pam3CSK-treated macrophage-like RAW264.7 cells without displaying cytotoxicity. Luteolin displayed potent NO-inhibitory activity and also suppressed the nuclear translocation of NF-κB (p65 and p50) via blockade of Src and Syk, but not other mitogen-activated kinases. Overexpression of wild type Src and point mutants thereof, and molecular modelling studies, suggest that the ATP-binding pocket may be the luteolin-binding site in Src. These results strongly suggest that luteolin may exert its anti-inflammatory action by suppressing the NF-κB signaling cascade via blockade of ATP binding in Src and Syk.

scholarly journals Controlling Neuropathic Pain by Adeno-Associated Virus Driven Production of the Anti-Inflammatory Cytokine, Interleukin-10

2005 ◽  
Vol 1 ◽  
pp. 1744-8069-1-9 ◽  
Author(s):  
Erin D Milligan ◽  
Evan M Sloane ◽  
Stephen J Langer ◽  
Pedro E Cruz ◽  
Marucia Chacur ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Interleukin 10 ◽  
Intrathecal Administration ◽  
Meningeal Cells ◽  
Novel Approach ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Pro Inflammatory Cytokines

Despite many decades of drug development, effective therapies for neuropathic pain remain elusive. The recent recognition of spinal cord glia and glial pro-inflammatory cytokines as important contributors to neuropathic pain suggests an alternative therapeutic strategy; that is, targeting glial activation or its downstream consequences. While several glial-selective drugs have been successful in controlling neuropathic pain in animal models, none are optimal for human use. Thus the aim of the present studies was to explore a novel approach for controlling neuropathic pain. Here, an adeno-associated viral (serotype II; AAV2) vector was created that encodes the anti-inflammatory cytokine, interleukin-10 (IL-10). This anti-inflammatory cytokine is known to suppress the production of pro-inflammatory cytokines. Upon intrathecal administration, this novel AAV2-IL-10 vector was successful in transiently preventing and reversing neuropathic pain. Intrathecal administration of an AAV2 vector encoding beta-galactosidase revealed that AAV2 preferentially infects meningeal cells surrounding the CSF space. Taken together, these data provide initial support that intrathecal gene therapy to drive the production of IL-10 may prove to be an efficacious treatment for neuropathic pain.

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