In silico identification of potential inhibitors for human aurora kinase b

Cell cycle progression through mitosis and meiosis involves regulation by serine/threonine kinases from the aurora family. Aurora kinase b (Aurkb) is mainly involved in the proper segregation of chromosomes during mitosis as well as meiosis. However, over expression of Aurkb leads to the unequal distribution of genetic information creating aneuploid cells, a hallmark of cancer. Thus, Aurkb can be used as an effective molecular target for computer-aided drug discovery against cancer. Existing Aurkb inhibitors are less efficient, hence an in silico work was carried out to identify novel potent inhibitors. Three published inhibitors azd1152, zm447439 and N-(4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy) quinazolin- 4-yl] amino} phenyl) benzamide were subjected to high throughput virtual screening of over 1 million entries from a ligand info meta database, to generate a 1161 compound library. The crystal structure was optimized and energy was minimized applying an OPLS force field in Maestro v9.0. Molecular docking using Glide was performed to predict the binding orientation of the prepared ligand molecule into a grid of 20*20*20 Å created around the centroid of the optimized human Aurkb protein. Nine lead molecules with good binding affinity with human Aurkb were identified. In silico pharmacokinetics study for these nine lead molecules has shown no ADME violation. Analysis of lead ‘1’- human Aurkb docking complex has revealed a XP Gscore of -10.20 kcal/mol with a highly stabilized hydrogen bond network with Asp218 and Ala157 and good Van der wall interactions. The docking complex coincides well with the native co- crystallized human Aurkb and inhibitor zm447439 complex. Thus, lead 1 would be highly useful for developing potential drug molecules for the treatment of cancer

Bidirectional motion of filaments: Role of motor proteins and passive cross linkers

In eukaryotic cells, motor proteins (MP) bind to cytoskeletal filaments and move along them in a directed manner generating active stresses. During cell division a spindle structure of overlapping antiparallel microtubules (MT) form whose stability and dynamics under the influence of MPs has been studied extensively. Although passive cross linkers (PCL) were known to provide structural stability to filamentous network, consequences of the interplay between ATP dependent active forces of MPs and passive entropic forces of PCLs on MT overlap remains largely unexplored. Here, we formulate and characterize a model to study this, using linear stability analysis and numerical integration. In presence of PCLs, we find dynamic phase transitions with changing activity exhibiting regimes of stable partial overlap with or without oscillations, instability towards complete overlap, and stable limit cycle oscillations that emerge via a supercritical Hopf bifurcation characterized by an oscillation frequency determined by the MP and PCL parameters. We show that the overlap dynamics and stability depend crucially on whether both the MTs of overlapping pair are movable or one is immobilized, having potential implications for in vivo and in vitro studies.Comment: 13 pages, 9 figure

Studies on mechanical behavior of glass epoxy composites with induced defects and correlations with NDT characterization parameters

Degradation in mechanical properties (compression, flexural and ILS) of glass epoxy composite laminates with induced defects (simulating delaminations) was studied. The defects were characterized by using the A-scan ultrasonic pulse-echo technique. The two A-scan parameters, viz. the back wall echo amplitude and time of flight, were followed respectively, as functions of the defect size (diameter) and its location in the laminate thickness. The mechanical properties of laminates were evaluated destructively for different defect sizes and locations. An attempt has been made to express the mechanical properties in terms of the two NDT scan parameters characterizing the defects and empirical equations presente

Plasma flows in the cool loop systems

We study the dynamics of low-lying cool loop systems for three datasets as observed by the Interface Region Imaging Spectrograph (IRIS). Radiances, Doppler shifts and line widths are investigated in and around observed cool loop systems using various spectral lines formed between the photosphere and transition region (TR). Footpoints of the loop threads are either dominated by blueshifts or redshifts. The co-spatial variation of velocity above the blue-shifted footpoints of various loop threads shows a transition from very small upflow velocities ranging from (-1 to +1) km/s in the Mg\,{\sc ii} k line (2796.20~\AA; formation temperature: log (T/K) = 4.0) to the high upflow velocities from (-10 to -20) km/s in Si\,{\sc iv}. Thus, the transition of the plasma flows from red-shift (downflows) to the blue-shift (upflows) is observed above the footpoints of these loop systems in the spectral line C\,{\sc ii} (1334.53~\AA; \log (T/K) = 4.3) lying between Mg\,{\sc ii} k and Si\,{\sc iv} (1402.77~\AA; log (T / K) = 4.8). This flow inversion is consistently observed in all three sets of the observational data. The other footpoint of loop system always remains red-shifted indicating downflowing plasma. The multi-spectral line analysis in the present paper provides a detailed scenario of the plasma flows inversions in cool loop systems leading to the mass transport and their formation. The impulsive energy release due to small-scale reconnection above loop footpoint seems to be the most likely cause for sudden initiation of the plasma flows evident at TR temperatures.Comment: 29 Pages, 14 figures, The Astrophysical Journal (in press