An integrated virtual screening protocol by combining molecular docking and pharmacophore mapping was established to identify novel inhibitors of JAK2 from a commercial compound database. Twelve novel and structurally diverse hits were selected and subjected to in vitro biological tests, and three compounds (A5, A6 and A9) with remarkable JAK2 inhibitory activity were identified. Then, the obtained structures were further used as the template for a subsequent similarity search, leading to the identification of another two promising compounds (B2 and B4). Selectivity profiles of JAK subtype and in vitro anti-cancer activity of the promising compounds were studied, revealing the promising compound B2 was of interest for further study because of its JAK2 selective profile, novelty of skeleton and significantly anti-proliferative effect against cancer cells. Finally, binding patterns of the compounds A5 and B2 were explored to provide a deeper insight for further structural optimization.
Study on the binding properties of helicid by pepsin systematically using multi-spectroscopic techniques and molecular docking method, and these interactions comprise biological recognition at molecular level and backbone of biological significance in medicine concerned with the uses, effects, and modes of action of drugs. We investigated the mechanism of interaction between helicid and pepsin by using various spectroscopic techniques viz., fluorescence spectra, UV-Vis absorption spectra, circular dichroism (CD), 3D spectra, synchronous fluorescence spectra and molecular docking methods. The quenching mechanism associated with the helicid-pepsin interaction was determined by performing fluorescence measurements at different temperatures. From the experimental results show that helicid quenched the fluorescence intensity of pepsin via a combination of static and dynamic quenching process. The binding constants (K) at three temperatures (288, 298, and 308 K) were 7.940 × 10, 2.082 × 10 and 3.199 × 10 L mol, respectively, and the number of binding sites (n) were 1.44, 1.14, and 1.18, respectively. The n value is close to unity, which means that there is only one independent class of binding site on pepsin for helicid. Thermodynamic parameters at 298 K were calculated as follows: ΔH (- 83.85 kJ mol), ΔG (- 33.279 kJ mol), and ΔS (- 169.72 J K mol). Based on thermodynamic analysis, the interaction of helicid with pepsin is driven by enthalpy, and Van der Waals' forces and hydrogen bonds are the main forces between helicid and pepsin. A molecular docking study further confirmed the binding mode obtained by the experimental studies. The conformational changes in the structure of pepsin was confirmed by 3D fluorescence spectra and circular dichroism.
The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound 4 that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of cancer cells. Moreover, compound 4 exhibited a promising in vivo anticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of cancer metastasis.
The cavitation performances and its internal flows in a centrifugal turbopump with and without a three-bladed axial inducer have been studied both experimentally and numerically. A 3D steady numerical model has been applied to simulate the cavitating flow from the inlet to the outlet ducts of the turbopump with and without an inducer by using ANSYS CFX code. In the present work, to clarify this relationship, we conducted experiments in both cold water ( T = 20°C) and hot water ( T = 80°C) with a focus on the development of vapor volume fraction and head degradation by gradually reducing the inlet pressure from atmospheric conditions to the minimum allowable value at a constant rate of about 3 mbar/s. The measured and predicted cavitation performances of the turbopump with and without an inducer have been compared under different operating conditions and the temperature of the operating fluid.
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