Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA

Indexación: Web of Science; Scopus.Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyano-fluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P3 (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S1, S2, and S3 subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure-activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations.We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin-inhibitor complexes. © 2015 Mena-Ulecia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.014277

Ultraluminous X-ray sources with flat-topped noise and QPO

We analyzed the X-ray power density spectra of five ultraluminous X-ray sources (ULXs) NGC5408 X-1, NGC6946 X-1, M82 X-1, NGC1313 X-1 and IC342 X-1 that are the only ULXs which display both flat-topped noise (FTN) and quasi-periodic oscillations (QPO). We studied the QPO frequencies, fractional root-mean-square (rms) variability, X-ray luminosity and spectral hardness. We found that the level of FTN is anti-correlated with the QPO frequency. As the frequency of the QPO and brightness of the sources increase, their fractional variability decreases. We propose a simple interpretation using the spherizarion radius, viscosity time and $\alpha$-parameter as basic properties of these systems. The main physical driver of the observed variability is the mass accretion rate which varies >3 between different observations of the same source. As the accretion rate decreases the spherization radius reduces and the FTN plus the QPO move toward higher frequencies resulting in a decrease of the fractional rms variability. We also propose that in all ULXs when the accretion rate is low enough (but still super-Eddington) the QPO and FTN disappear. Assuming that the maximum X-ray luminosity depends only on the black hole (BH) mass and not on the accretion rate (not considering the effects of either the inclination of the super-Eddington disc nor geometrical beaming of radiation) we estimate that all the ULXs have about similar BH masses, with the exception of M82 X-1, which might be 10 times more massive.Comment: 15 pages, 7 figures, accepted for publication in MNRA

The Role of External Economies in U.S. Manufacturing

This paper develops a method for joint estimation of both the degree of internal returns to scale and the extent of external economies. We apply the method in estimating returns to scale indexes for U.S. manufacturing industries at the two-digit level. Overall, we find that only three of the twenty industry categories show any evidence of internal increasing returns: (1) Primary Metals, (2) Electrical Machinery, and (3) Paper Products. More striking, however, is the very strong evidence of the existence of external economies, where external is defined as external to a given two-digit industry and internal to the U.S.. According to our preferred estimates, if all manufacturing industries simultaneously raise their inputs by 10%, aggregate manufacturing production rises by 13%, of which about 5% is due to external economies. Thus, when an industry increases its inputs in isolation by 10%, its output rises by no more than 8%.

Zombie Lending and Depressed Restructuring in Japan

In this paper, we propose a bank-based explanation for the decade-long Japanese slowdown following the asset price collapse in the early 1990s. We start with the well-known observation that most large Japanese banks were only able to comply with capital standards because regulators were lax in their inspections. To facilitate this forbearance the banks often engaged in sham loan restructurings that kept credit flowing to otherwise insolvent borrowers (that we call zombies). Thus, the normal competitive outcome whereby the zombies would shed workers and lose market share was thwarted. Our model highlights the restructuring implications of the zombie problem. The counterpart of the congestion created by the zombies is a reduction of the profits for healthy firms, which discourages their entry and investment. In this context, even solvent banks do not find good lending opportunities. We confirm our story's key predictions that zombie-dominated industries exhibit more depressed job creation and destruction, and lower productivity. We present firm-level regressions showing that the increase in zombies depressed the investment and employment growth of non-zombies and widened the productivity gap between zombies and non-zombies.

Neutrino Scattering in Heterogeneous Supernova Plasmas

Neutrinos in core collapse supernovae are likely trapped by neutrino-nucleus elastic scattering. Using molecular dynamics simulations, we calculate neutrino mean free paths and ion-ion correlation functions for heterogeneous plasmas. Mean free paths are systematically shorter in plasmas containing a mixture of ions compared to a plasma composed of a single ion species. This is because neutrinos can scatter from concentration fluctuations. The dynamical response function of a heterogeneous plasma is found to have an extra peak at low energies describing the diffusion of concentration fluctuations. Our exact molecular dynamics results for the static structure factor reduce to the Debye Huckel approximation, but only in the limit of very low momentum transfers.Comment: 11 pages, 13 figure

Generalized scattering-matrix approach for magneto-optics in periodically patterned multilayer systems

We present here a generalization of the scattering-matrix approach for the description of the propagation of electromagnetic waves in nanostructured magneto-optical systems. Our formalism allows us to describe all the key magneto-optical effects in any configuration in periodically patterned multilayer structures. The method can also be applied to describe periodic multilayer systems comprising materials with any type of optical anisotropy. We illustrate the method with the analysis of a recent experiment in which the transverse magneto-optical Kerr effect was measured in a Fe film with a periodic array of subwavelength circular holes. We show, in agreement with the experiments, that the excitation of surface plasmon polaritons in this system leads to a resonant enhancement of the transverse magneto-optical Kerr effect.Comment: 12 pages, 6 figures, submitted to Physical Review