Dynamic and multi-pharmacophore modeling for designing polo-box domain inhibitors.

The polo-like kinase 1 (Plk1) is a critical regulator of cell division that is overexpressed in many types of tumors. Thus, a strategy in the treatment of cancer has been to target the kinase activity (ATPase domain) or substrate-binding domain (Polo-box Domain, PBD) of Plk1. However, only few synthetic small molecules have been identified that target the Plk1-PBD. Here, we have applied an integrative approach that combines pharmacophore modeling, molecular docking, virtual screening, and in vitro testing to discover novel Plk1-PBD inhibitors. Nine Plk1-PBD crystal structures were used to generate structure-based hypotheses. A common pharmacophore model (Hypo1) composed of five chemical features was selected from the 9 structure-based hypotheses and used for virtual screening of a drug-like database consisting of 159,757 compounds to identify novel Plk1-PBD inhibitors. The virtual screening technique revealed 9,327 compounds with a maximum fit value of 3 or greater, which were selected and subjected to molecular docking analyses. This approach yielded 93 compounds that made good interactions with critical residues within the Plk1-PBD active site. The testing of these 93 compounds in vitro for their ability to inhibit the Plk1-PBD, showed that many of these compounds had Plk1-PBD inhibitory activity and that compound Chemistry_28272 was the most potent Plk1-PBD inhibitor. Thus Chemistry_28272 and the other top compounds are novel Plk1-PBD inhibitors and could be used for the development of cancer therapeutics

Verification of specific G-quadruplex structure by using a novel cyanine dye supramolecular assembly: II. The binding characterization with specific intramolecular G-quadruplex and the recognizing mechanism

The supramolecular assembly of a novel cyanine dye, 3,3′-di(3-sulfopropyl)-4,5,4′,5′-dibenzo-9-ethyl-thiacarbocyanine triethylammonium salt (ETC) was designed to verify specific intramolecular G-quadruplexes from duplex and single-strand DNAs. Spectral results have shown that ETC presented two major distinct signatures with specific intramolecular G-quadruplexes in vitro: (i) dramatic changes in the absorption spectra (including disappearance of absorption peak around 660 nm and appearance of independent new peak around 584 nm); (ii) ∼70 times enhancement of fluorescence signal at 600 nm. Furthermore, based on 1H-nuclear magnetic resonance and circular dichroism results, the preferring binding of ETC to specific intramolecular G-quadruplexes probably result from end-stacking, and the loop structure nearby also plays an important role

A Coupled-Inductor Interleaved LLC Resonant Converter for Wide Operation Range

In this paper, a coupled-inductor interleaved LLC resonant converter (CI-ILLC) was proposed, which can achieve extensive operation range applications by multiplexing inductors and switches. In this proposed CI-ILLC, the coupled-inductor not only serves as a filter inductor but also plays the role of transformer to improve the power density. By changing the modulation methods, the proposed converter can work at three modes for a wide operation range, namely high gain (HG) mode, medium gain (MG) mode, and low gain (LG) mode. Moreover, the interleaved structure greatly reduces the current ripple and current stress of switches. Besides, in HG and MG modes, all switches can realize zero-voltage switching, with high energy transmission efficiency. Finally, the simulation and experiment results of the prototype with 120–200 V input and 50–200 V output are presented to verify the viability of the proposed converter

Two-Layer Cooperative Optimization of Flexible Interconnected Distribution Networks Considering Electric Vehicle User Satisfaction Degree

The scaled access of electric vehicles (EVs) exacerbates load fluctuations in distribution networks, which is not conducive to the stable and economic operation of the distribution networks. At present, user satisfaction degree is generally low. To avoid this problem, this paper proposed a two-layer cooperative optimization of flexible interconnected distribution networks considering EV user satisfaction degree. First, the EV user satisfaction degree model is established by considering EV users’ charging waiting time, charging power, and other indicators. At the same time, an EV charging mode switching model is constructed based on the number of EVs entering the network and their battery charge state. On this basis, the Monte Carlo algorithm is used to generate the results of the daily distribution of EV loads taking into account the user satisfaction degree, so as to improve the load ratio of the transformer in the distribution network. Further, a two-layer cooperative optimization of flexible interconnected distribution networks considering electric vehicle user satisfaction degree is developed with the daily operating cost of each network as the optimization objective. Finally, a flexible interconnected power distribution network consisting of three power distribution networks is used as an example for validation. The results show that this method is effective in improving EV user satisfaction degree and reducing the peak-to-valley ratio of the system load while taking into account the safe and economic operation of the distribution network, which greatly improves the reliability and economy of the operation of the flexible interconnected power distribution network

Thrombin Ultrasensitive Detection Based on Chiral Supramolecular Assembly Signal-Amplified Strategy Induced by Thrombin-Binding Aptamer

Thrombin plays a critical role in hemostasis and hemolysis. It is of high importance to develop a system toward thrombin detection with high sensitivity and high selectivity for both research and clinical diagnosis applications. In this paper, we developed a thrombin detection assay by taking advantage of the novel signal amplified strategy based on the chiral supramolecular assembly in physiological K⁺ background. This assay could detect thrombin as low concentration as about 2 pM and provided a highly specific selectivity among several common interferences. Furthermore, the assay can discriminate thrombin from other nonspecific analogous proteins with high selectivity and can be used to detect thrombin in diluted real human serum samples, which suggested its great potential for rapid detection of thrombin in the clinic