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The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consistent with a noncompetitive allosteric mode(More)
BACKGROUND AND PURPOSE DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. EXPERIMENTAL APPROACH The binding mode, molecular mechanism of action and selectivity were investigated(More)
Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1(More)
Activation of complement via the innate and adaptive immune system is vital to the body's defences in fighting infections. Unregulated complement activation is likely to play a crucial role in the pathogenesis of several diseases including psoriasis, adult (acute) respiratory distress syndrome (ARDS), bullous pemphigoid (BP), rheumatoid arthritis (RA) and(More)
We collected 1173 hERG patch clamp (PC) data (IC50) from the literature to derive twelve classification models for hERG inhibition, covering a large variety of chemical descriptors and classification algorithms. Models were generated using 545 molecules and validated through 258 external molecules tested in PC experiments. We also evaluated the suitability(More)
The TRPM8 cation channel belongs to the superfamily of transient receptor potential (TRP) channels. It is involved in non-painful cool sensation and triggered by diverse chemical and physical stimuli whose precise activation mechanism is still unknown. The study presents a set of targeted molecular dynamics (MD) simulations involving selected complexes of(More)
Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent(More)
BACKGROUND Neutrophil recruitment mediated by the CXCL1/KC chemokine and its receptors CXCR1/CXCR2 plays a critical role in inflammatory diseases. Recently, neutrophil migration and activation triggered by CXCL1-CXCR1/2 signalling was implicated in inflammatory nociception; however, their role in post-surgical pain has not been elucidated. In this study, we(More)
In the last decade, accumulated evidence highlighted that GPR55 might be activated by several classical cannabinoid ligands, making this orphan receptor the main candidate to be considered as the "third" cannabinoid receptor. The investigation of its pharmacology has often provided divergent and more intricate results that have complicated the understanding(More)
A novel class of 2-(R)-phenylpropionamides has been recently reported to inhibit in vitro and in vivo interleukin-8 (CXCL8)-induced biological activities. These CXCL8 inhibitors are derivatives of phenylpropionic nonsteroidal antiinflammatory drugs (NSAIDs), high-affinity ligands for site II of human serum albumin (HSA). Up to date, only a limited number of(More)