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It is a great challenge to induce the formation of the RuP4 phase and realize the construction of a metal‐rich phase/phosphorus‐rich phase‐ruthenium phosphide heterostructure by directional regulation of the proportion of P and metal atoms. The ultra‐high conductivity of Ru2P and the excellent ability of V‐doped RuP4 to absorb/desorb H* are confirmed by density functional theory (DFT) calculations, which laid a theoretical foundation for the construction of a unique Ru2P/V‐RuP4 structure to accelerate HER reaction kinetics. This work innovatively uses the V‐doping strategy to induce the formation of RuP4 phase with high intrinsic activity, and finally construct V‐RuxPy nanosheets with rich Ru/Ru2P/V‐RuP4 heterostructures. Thanks to the rich Ru/Ru2P/V‐RuP4 heterostructure and the optimization of V dopants, the V‐RuxPy catalyst only needs 180 mV to obtain an industrial‐grade current density of 1 A cm−2. In summary, this work provides a new idea for the design and performance optimization of ruthenium‐based catalysts. [ABSTRACT FROM AUTHOR]

The interface engineering strategy is deemed to be a direct approach for boosting the water splitting activity of materials, but it is still a challenge to achieve both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) activities exceeding those of precious-metal catalysts. Herein, a tunable photodeposition method was utilized for the construction of Ru@FeCoP with rich Ru/FeCoP heterointerfaces. Strikingly, the η100 value of Ru@FeCoP was only 0.0741 V for the HER and 0.314 V for OER, which was reduced by 63.8% and 55.2% compared to Pt/C and RuO2 benchmarks, respectively. The mechanism investigation revealed that Ru at the Ru/FeCoP heterointerfaces not only offers highly active sites for HER but also pulls electrons from FeCoP, which facilitates the generation of Fe and Co with high valency, thereby increasing the OER activity. This work overcomes the problem of low water-splitting efficiency of precious metals by constructing a metal/phosphide heterostructure to drive a dual-active site mechanism and provides an effective route for the preparation of high-performance water-dissociation electrocatalysts. [ABSTRACT FROM AUTHOR]

Recent crystallography studies have shown that the binding site oxyanion hole plays an important role in inhibitor binding, but can exist in two conformations (active/inactive). We have undertaken molecular dynamics (MD) calculations to better understand oxyanion hole dynamics and thermodynamics. We find that the Zika virus (ZIKV) NS2B/NS3 protease maintains a stable closed conformation over multiple 100‐ns conventional MD simulations in both the presence and absence of inhibitors. The S1, S2, and S3 pockets are stable as well. However, in two of eight simulations, the A132‐G133 peptide bond in the binding pocket of S1' spontaneously flips to form a 310‐helix that corresponds to the inactive conformation of the oxyanion hole, and then maintains this conformation until the end of the 100‐ns conventional MD simulations without inversion of the flip. This conformational change affects the S1' pocket in ZIKV NS2B/NS3 protease active site, which is important for small molecule binding. The simulation results provide evidence at the atomic level that the inactive conformation of the oxyanion hole is more favored energetically when no specific interactions are formed between substrate/inhibitor and oxyanion hole residues. Interestingly, however, transition between the active and inactive conformation of the oxyanion hole can be observed by boosting the valley potential in accelerated MD simulations. This supports a proposed induced‐fit mechanism of ZIKV NS2B/NS3 protease from computational methods and provides useful direction to enhance inhibitor binding predictions in structure‐based drug design. [ABSTRACT FROM AUTHOR]

Background: A new approach targeting aeroallergen sensing in the early events of mucosal immunity could have greater benefit. The CSF1‐CSF1R pathway has a critical role in trafficking allergens to regional lymph nodes through activating dendritic cells. Intervention in this pathway could prevent allergen sensitization and subsequent Th2 allergic inflammation. Objective: To examine the therapeutic effectiveness of CSF1 and CSF1R inhibition for blocking the dendritic cell function of sensing aeroallergens. Methods: We adopted a model of chronic asthma induced by a panel of three naturally occurring allergens and novel delivery system of CSF1R inhibitor encapsulated nanoprobe. Results: Selective depletion of CSF1 in airway epithelial cells abolished the production of allergen‐reactive IgE, resulting in prevention of new asthma development as well as reversal of established allergic lung inflammation. CDPL‐GW nanoprobe containing GW2580, a selective CSF1R inhibitor, showed favorable pharmacokinetics for inhalational treatment and intranasal insufflation delivery of CDPL‐GW nanoprobe ameliorated asthma pathologies including allergen‐specific serum IgE production, allergic lung and airway inflammation and airway hyper‐responsiveness (AHR) with minimal pulmonary adverse reaction. Conclusion: The inhibition of the CSF1‐CSF1R signaling pathway effectively suppresses sensitization to aeroallergens and consequent allergic lung inflammation in a murine model of chronic asthma. CSF1R inhibition is a promising new target for the treatment of allergic asthma. [ABSTRACT FROM AUTHOR]

(+)-Digoxin ( 1 ) is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides ( 2 - 5 ) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin ( 6 ) and (+)-17- epi -20,22-dihydro-21α-hydroxydigoxin ( 7 ), were synthesized from 1 and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure-activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for 1 to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic 1 and the noncytotoxic derivative 7 bind differentially to Na + /K + -ATPase. The HO-12β, HO-14β, and HO-3'aα hydroxy groups of (+)-digoxin ( 1 ) may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na + /K + -ATPase, respectively, but the altered lactone unit of 7 results in a rotation of its steroid core, which depotentiates the binding between this compound and Na + /K + -ATPase. Thus, 1 was found to inhibit Na + /K + -ATPase, but 7 did not. In addition, the cytotoxic 1 did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na + /K + -ATPase but not by interacting with glucose transporters.

High-throughput screening assays have become nearly ubiquitous in the search for small compounds or peptides that can modulate biological processes for therapeutic purposes. While many assays have become quite robust, with well-established protocols, the subsequent steps of validating the hits and choosing the best ones to take forward into leads for further chemical development are less established. In this chapter, we describe a variety of approaches, including chemical assessment, the use of various computational approaches, a variety of counter-screens, and "orthogonal" biophysical assays using nuclear magnetic resonance, surface plasmon resonance, isothermal titration calorimetry or thermal shift assays as methods for validating and assessing the quality of hits., (© 2018 Elsevier Inc. All rights reserved.)

To investigate the effects of configuration on bioactivity, spirooliganones A and B and their six diastereoisomers (1-8) were synthesized in 11 steps. The key benzopyran core was assembled by intermolecular [4 + 2] hetero-Diels-Alder cycloaddition between (-)-sabinene and o-quinone methide, which was generated from the corresponding o-hydroxybenzyl alcohol. After establishing the absolute configuration, the inhibitory activities of spirooliganones 1-8 against Coxsackie virus B3 were evaluated, and the primary structure-activity relationships were analyzed. Compound 3 was the most potent compound, with an IC50 of 0.41 μM.

Novel glycyrrhizin (GL) derivatives were designed and synthesized by introducing various amine or amino acid residues into the carbohydrate chain and at C-30. Their inhibitory effects on high-mobility group box 1 (HMGB1) were evaluated using a cell-based lipopolysaccharide (LPS) induced tumor necrosis factor α (TNF-α) release study. Compounds 10, 12, 18-20, 23, and 24, which had substituents introduced at C-30, demonstrated moderate HMGB1 inhibition with ED₅₀ values ranging from 337 to 141 μM, which are values comparable to that of the leading GL compound (1) (ED₅₀ = 70 μM). Compounds 23 and 24 emerged as novel and interesting HMGB1 inhibitors. These compounds were able to extend the survival of mice with chronic heart failure (CHF) and acute heart failure (AHF), respectively. In addition, molecular modeling studies were performed to support the biological data.