Allergic asthma, a chronic inflammatory illness that affects millions worldwide, has serious economic and health consequences. Despite advances in therapy, contemporary treatments have poor efficacy and negative effects. This study investigates hematopoietic prostaglandin D2 synthase (HPGDS) as a potential target for novel asthma therapies. Targeting HPGDS may provide innovative treatment methods. A library of phytochemicals was used to find putative HPGDS inhibitors by structure-based and ligand-based virtual screening. Among the 2295 compounds screened, four compounds (ZINC208828240, ZINC95627530, ZINC14727536, and ZINC14711790) demonstrated strong binding affinities of -10.4, -10.3, -9.2, -9.1 kcal/mol respectively with key residues, suggesting their potential as a highly effective HPGDS inhibitor. Molecular dynamics (MD) simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) computations were further performed to evaluate the stability and binding affinity of the complexes. MD simulations and MMPBSA confirmed that compound ZINC14711790 showed high stability and binding affinity (binding energy -31.52 kcal/mol) than other compounds, including HQL-79, suggesting that this compound might be used as promising inhibitors to treat asthma. RMSD and RMSF analysis also revealed that ZINC14711790 exhibited strong dynamic stability. The findings of this study show the efficacy of ZINC14711790 as HPGDS inhibitors with high binding affinity, dynamic stability, and appropriate ADMET profile.

2019-11-01·The FASEB Journal

Crth2 receptor signaling down‐regulates lipopolysaccharide‐induced NF‐αB activation in murine macrophages via changes in intracellular calcium

Article

作者: Lee, Tai‐Jung ; Nettleford, Shaneice ; Huffnagle, Ian ; Berry, Svanjita ; Qian, Fenghua ; Paulson, Robert F. ; Trebak, Mohamed ; Yoast, Ryan ; Prabhu, K. Sandeep ; Diwakar, Bastihalli T. ; Rossi, Randall M.

Prostaglandin D2 and its cyclopentenone metabolites [cyclopentenone prostaglandins (CyPGs)], Δ12prostaglandin J2 and 15‐deoxy‐Δ12, 14‐prostaglandin J2, act through2GPCRs, d‐type prostanoid 1 and the chemoattractant receptor homologous molecule expressed on type 2 T‐helper cells (Crth2). In addition to its role in allergy and asthma, the role of Crth2 in the resolution of inflammation, to mediate the proresolving functions of endogenous CyPGs, is not well understood. We investigated the regulation of LPS or zymosan‐induced inflammatory response by signals from the Crth2 receptor in macrophages that lack Crth2 expression [knockout (KO)]. Increased expression of proinflammatory genes, including Tnf‐α, was observed in Crth2 KO cells. Targeting the endogenous biosynthetic pathway of CyPGs with indomethacin or HQL79, which inhibit cyclooxygenases or hematopoietic prostaglandin D synthase, respectively, or use of Crth2 antagonists recapitulated the proinflammatory phenotype as in Crth2 KO cells. Ligand‐dependent activation of Crth2 by 13, 14‐dihydro‐15‐keto‐prostaglandin D2 increased Ca2+ influx through store‐operated Ca2+ entry (SOCE) accompanied by the up‐regulation of stromal interaction molecule 1 and calcium release‐activated calcium modulator 1 expression, suggesting that the proresolution effects of CyPG‐dependent activation of SOCE could be mediated by Crth2 during inflammation. Interestingly, Crth2 signaling down‐regulated the Ca2+‐regulated heat stable protein 1 that stabilizes Tnf‐α mRNA via the increased expression of microRNA 155 to dampen inflammatory responses triggered through the TNF‐α‐NF‐αB axis. In summary, these studies present a novel regulatory role for Crth2 during inflammatory response in macrophages.—Diwakar, B. T., Yoast, R., Nettleford, S., Qian, F., Lee, T.‐J., Berry, S., Huffnagle, I., Rossi, R. M., Trebak, M., Paulson, R. F., Prabhu, K. S. Crth2 receptor signaling down‐regulates lipopolysaccharide‐induced NF‐αB activation in murine macrophages via changes in intracellular calcium. FASEB J. 33, 12838–12852 (2019). www.fasebj.org

2018-12-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Lipocalin-Like Prostaglandin D Synthase but Not Hemopoietic Prostaglandin D Synthase Deletion Causes Hypertension and Accelerates Thrombogenesis in Mice

3区 · 医学

Article

作者: Grant, Gregory R ; Song, Wen-Liang ; FitzGerald, Garret A ; Ricciotti, Emanuela ; Liang, Xue ; Grosser, Tilo

Prostaglandin (PG) D₂ is formed by two distinct PGD synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD₂-producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a σ glutathione-S-transferase. PGD₂ plays an important role in the maintenance of vascular function; however, the relative contribution of L-PGDS- and H-PGDS-dependent formation of PGD₂ in this setting is unknown. To gain insight into the function played by these distinct PGDS, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds knockout (KO) mice. Deletion of L-Pgds depresses urinary PGD₂ metabolite (PGDM) by ∼35%, whereas deletion of H-Pgds does so by ∼90%. Deletion of L-Pgds, but not H-Pgds, elevates BP and accelerates the thrombogenic occlusive response to a photochemical injury to the carotid artery. HQL-79, a H-PGDS inhibitor, further depresses PGDM in L-Pgds KO mice, but has no effect on BP or on the thrombogenic response. Gene expression profiling reveals that pathways relevant to vascular function are dysregulated in the aorta of L-Pgds KOs. These results indicate that the functional impact of L-Pgds deletion on vascular homeostasis may result from an autocrine effect of L-PGDS-dependent PGD₂ on the vasculature and/or the L-PGDS function as lipophilic carrier protein.

100 项与 HQL-79 相关的药物交易

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