Parallel DNS using a compressible turbulent channel flow benchmark

In recent years, the increased use of off-the-shelf components and the large-scale adoption of parallel computing have led to a dramatic reduction in the costs associated with high-performance computing. This has enabled increased usage of compute-intensive methods, such as Direct Numerical Simulation (DNS), for the simulation of turbulent flows. We introduce a sophisticated DNS code that incorporates a number of advanced features:high-order central differencing; a shock-preserving advection scheme from the total variation diminishing (TVD) family; entropy splitting of the Euler terms and the associated stable boundary treatment

On the performance of WENO/TENO schemes to resolve turbulence in DNS/LES of high-speed compressible flows

High‐speed compressible turbulent flows typically contain discontinuities and have been widely modelled using Weighted Essentially Non‐Oscillatory (WENO) schemes due to their high‐order accuracy and sharp shock capturing capability. However, such schemes may damp the small scales of turbulence, and result in inaccurate solutions in the context of turbulence‐resolving simulations. In this connection, the recently‐developed Targeted Essentially Non‐Oscillatory (TENO) schemes, including adaptive variants, may offer significant improvements. The present study aims to quantify the potential of these new schemes for a fully‐turbulent supersonic flow. Specifically, DNS of a compressible turbulent channel flow with M = 1: 5 and Re τ = 222 is conducted using OpenSBLI, a high‐order finite difference CFD framework. This flow configuration is chosen to decouple the effect of flow discontinuities and turbulence and focus on the capability of the aforementioned high‐order schemes to resolve turbulent structures. The effect of the spatial resolution in different directions and coarse grid implicit LES are also evaluated against theWALE LES model. The TENO schemes are found to exhibit significant performance improvements over the WENO schemes in terms of the accuracy of the statistics and the resolution of the three‐dimensional vortical structures. The 6th order adaptive TENO scheme is found to produce comparable results to those obtained with non‐dissipative 4th and 6th order central schemes and reference data obtained with spectral methods. Although the most computationally expensive scheme, it is shown that this adaptive scheme can produce satisfactory results if used as an implicit LES model

The roles of type 2 cytotoxic T cells in inflammation, tissue remodeling, and prostaglandin (PG) D2 production are attenuated by PGD2 receptor 2 antagonism

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD2 and its receptor PGD2 receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD2/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to TCR-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD2 but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma

Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding

Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein−ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the β2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure−activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure−activity relationships of β2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions

Fevipiprant (QAW039), a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [3H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2 (PGD2). The binding kinetics of QAW039 determined directly using [3H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 107 M-1min-1 and 0.048 minute-1, respectively. Importantly, the koff of QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [35S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2 concentrations, which may be clinically relevant

Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2 receptor antagonist for treatment of asthma

Further optimization of an initial DP2 receptor antagonist clinical candidate NVPQAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma