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Natural products are widely used for treating mitochondrial dysfunction-related diseases and cancers. Curcumin, a well-known natural product, can be potentially used to treat cancer. Human salt-induced kinase 3 (SIK3) is one of the target proteins for curcumin. However, the interactions between curcumin and human SIK3 have not yet been investigated in detail. In this study, we studied the binding models for the interactions between curcumin and human SIK3 using computational tools such as homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations. The open activity loop conformation of SIK3 with the ketoenol form of curcumin was the optimal binding model. The I72, V80, A93, Y144, A145, and L195 residues played a key role for curcumin binding with human SIK3. The interactions between curcumin and human SIK3 were also investigated using the kinase assay. Moreover, curcumin exhibited an IC50 (half-maximal inhibitory concentration) value of 131 nM, and it showed significant antiproliferative activities of 9.62 ± 0.33 µM and 72.37 ± 0.37 µM against the MCF-7 and MDA-MB-23 cell lines, respectively. This study provides detailed information on the binding of curcumin with human SIK3 and may facilitate the design of novel saltinducible kinases inhibitors. [ABSTRACT FROM AUTHOR]

Lysophosphatidylserine (LysoPS) is an endogenous pan-agonist of three G-protein coupled receptors (GPCRs): LPS 1 /GPR34, LPS 2 /P2Y 10 , and LPS 3 /GPR174, and we previously reported a series of LysoPS-based agonists of these receptors. Interestingly, we found that LPS 1 agonist activity was very sensitive to structural change at the hydrophobic fatty acid moiety, whereas LPS 2 agonist activity was not. Here, to probe the molecular basis of LPS 2 agonist binding, we developed a new class of hydrophobic fatty acid surrogates having a biphenyl-ether scaffold. The LPS 2 agonist activity of these compounds proved sensitive to molecular modification of the hydrophobic skeleton. Thus, we next constructed an LPS 2 model by homology modeling and docking/molecular dynamics (MD) simulation, and validated it by means of SAR studies together with point mutations of selected receptor amino-acid residues. The putative ligand-binding site of LPS 2 is Γ-shaped, with a hydrophilic site horizontally embedded in the receptor transmembrane helix bundles and a perpendicular hydrophobic groove adjoining transmembrane domains 4 and 5 that is open to the membrane bilayer. The binding poses of LPS 2 agonists to this site are consistent with easy incorporation of various kinds of fatty acid surrogates. Structural development based on this model afforded a series of potent and selective LPS 2 full agonists, which showed enhanced in vitro actin stress fiber formation effect. [Display omitted] • A biphenyl-ether skeleton of LPS 2 -selective agonist was found to amplify the activity change upon structural modifications of the hydrophobic moiety. • Docking studies and point mutation of the receptor elucidated LPS 2 agonist binding mode as representing a hydrophilic site parallel to membrane bilayer and a perpendicular hydrophobic groove between transmembrane helices 4 & 5. • Binding model-guided-ligand design led to the development of potent and selective LPS 2 agonists with improved actin stress fiber formation activity. [ABSTRACT FROM AUTHOR]

Long-span air supported membrane structures are typical wind sensitive buildings, wind load is often their control load. The existing analysis of air supported membrane structures basically assumes that the nodes of the cable net and membrane are bound together, the slide or separation between the cable net and the membrane under wind load is not considered. The lack of cable–membrane​ contact model causes hidden danger to the safety of wind resistance performance of long-span air supported membrane structures. In this paper, ANSYS software is adopted for structural analysis, the cable net of air supported membrane structure is divided into many small cable segments, and nodes of all cable segments form point-surface contact pairs with the membrane surface, the joints of all cable segments may bond, slide or separate from the membrane surface. The cable–membrane contact model is used to analyze the wind-induced response of an air supported membrane structure with orthogonal cable net, and the results are compared with the wind-induced response of the cable–membrane binding model. The analysis results of the two models show that: when the cable–membrane contact model is adopted, the displacement and stress responses of the membrane are greatly increased under strong wind load due to the separation of the membrane and the cable net, the axial force distribution of the cable is more uniform due to the sliding between the cable net and membrane. The cable–membrane binding model overestimates the restraint effect of cable net on membrane, in order to better optimize the design of long-span air supported membrane structures, it is necessary to consider adopting cable–membrane contact model. • Cable–membrane contact model was established for air-supported membrane structures. • Pressure distribution of an air-supported structure was obtained by wind tunnel test. • Wind vibration responses analysis was solved adopting slow dynamic method. • The results using cable–membrane contact model were compared with those using cable–membrane binding model. • Displacement response of membrane increases significantly adopting cablemembrane contact model. [ABSTRACT FROM AUTHOR]

• The three compartment PK model is extended to delivery to two cell types. • The model is applied to mixed cell populations (drug resistant and drug responsive) • High proportions of responsive cells can deplete extracellular drug concentrations. • High proportions of responsive cells can lower drug metabolized in resistant cells. The rate of drug delivery to cells and the subsequent rate of drug metabolism are dependent on the cell membrane permeability to the drug. In some cases, tissue may be composed of different types of cells that exhibit order of magnitude differences in their membrane permeabilities. This paper presents a brief review of the components of the tissue scale three-compartment pharmacokinetic model of drug delivery to single–cell–type populations. The existing model is extended to consider tissue composed of two different cell types. A case study is presented of infusion mediated delivery of doxorubicin to a tumor that is composed of a drug reactive cell type and of a drug resistive cell type. The membrane permeabilities of the two cell types differ by an order of magnitude. A parametric investigation of the population composition is conducted and it is shown that the drug metabolism of the low permeability cells are negatively influenced by the fraction of the tissue composed of the permeable drug reactive cells. This is because when the population is composed mostly of drug permeable cells, the extracellular space is rapidly depleted of the drug. This has two compounding effects: (i) locally there is simply less drug available to the neighboring drug resistant cells, and (ii) the depletion of the drug from the extracellular space near the vessel-tissue interface leaves less drug to be transported to both cell types farther away from the vessel. [ABSTRACT FROM AUTHOR]

Microbial bioremediation is a very potent and eco-friendly approach to alleviate pesticide pollution in agricultural ecosystems, and hydrolase is an effective element for contaminant degradation. In the present study, a novel Mn 2+ -dependent esterase, PchA, that efficiently hydrolyzes carbamate pesticides with aromatic structures was identified from Pseudomonas sp. PS21. The hydrolytic activity was confirmed to be related closely to the core catalytic domain, which consists of six residues. The crucial residues indirectly stabilized the position of carbaryl via chelating Mn 2+ according to the binding model clarified by molecular simulations, and the additional hydrophobic interactions between carbaryl with several hydrophobic residues also stabilized the binding conformation. The residue Glu398, by serving as the general base, might activate a water molecule and facilitate PchA catalysis. This work offers valuable insights into the binding interaction and hydrolytic mechanism of carbaryl with the hydrolase PchA and will be crucial to designing strategies leading to the protein variants that are capable of degrading related contaminants.