Comparative molecular field analysis of a series of inhibitors of HIV-1 protease

Several protease inhibitors have reached the world market in the last fifteen years, dramatically improving the quality of life and life expectancy of millions of HIV-infected patients. In spite of the tremendous research efforts in this area, resistant HIV-1 variants are constantly decreasing the ability of the drugs to efficiently inhibit the enzyme. As a consequence, inhibitors with novel frameworks are necessary to circumvent resistance to chemotherapy. In the present work, we have created 3D QSAR models for a series of 82 HIV-1 protease inhibitors employing the comparative molecular field analysis (CoMFA) method. Significant correlation coefficients were obtained (q(2) = 0.82 and r(2) = 0.97), indicating the internal consistency of the best model, which was then used to evaluate an external test set containing 17 compounds. The predicted values were in good agreement with the experimental results, showing the robustness of the model and its substantial predictive power for untested compounds. The final QSAR model and the information gathered from the CoMFA contour maps should be useful for the design of novel anti-HIV agents with improved potency.

An extinction-survival-type phase transition in the probabilistic cellular automaton p182-q200

We investigate the critical behaviour of a probabilistic mixture of cellular automata (CA) rules 182 and 200 (in Wolfram`s enumeration scheme) by mean-field analysis and Monte Carlo simulations. We found that as we switch off one CA and switch on the other by the variation of the single parameter of the model, the probabilistic CA (PCA) goes through an extinction-survival-type phase transition, and the numerical data indicate that it belongs to the directed percolation universality class of critical behaviour. The PCA displays a characteristic stationary density profile and a slow, diffusive dynamics close to the pure CA 200 point that we discuss briefly. Remarks on an interesting related stochastic lattice gas are addressed in the conclusions.

VELOCITY FIELD OF COMPRESSIBLE MAGNETOHYDRODYNAMIC TURBULENCE: WAVELET DECOMPOSITION AND MODE SCALINGS

We study compressible magnetohydrodynamic turbulence, which holds the key to many astrophysical processes, including star formation and cosmic-ray propagation. To account for the variations of the magnetic field in the strongly turbulent fluid, we use wavelet decomposition of the turbulent velocity field into Alfven, slow, and fast modes, which presents an extension of the Cho & Lazarian decomposition approach based on Fourier transforms. The wavelets allow us to follow the variations of the local direction of the magnetic field and therefore improve the quality of the decomposition compared to the Fourier transforms, which are done in the mean field reference frame. For each resulting component, we calculate the spectra and two-point statistics such as longitudinal and transverse structure functions as well as higher order intermittency statistics. In addition, we perform a Helmholtz-Hodge decomposition of the velocity field into incompressible and compressible parts and analyze these components. We find that the turbulence intermittency is different for different components, and we show that the intermittency statistics depend on whether the phenomenon was studied in the global reference frame related to the mean magnetic field or in the frame defined by the local magnetic field. The dependencies of the measures we obtained are different for different components of the velocity; for instance, we show that while the Alfven mode intermittency changes marginally with the Mach number, the intermittency of the fast mode is substantially affected by the change.

Sound waves and solitons in hot and dense nuclear matter

Assuming that nuclear matter can be treated as a perfect fluid, we study the propagation of perturbations in the baryon density. The equation of state is derived from a relativistic mean field model, which is a variant of the non-linear Walecka model. The expansion of the Euler and continuity equations of relativistic hydrodynamics around equilibrium configurations leads to differential equations for the density perturbation. We solve them numerically for linear and spherical perturbations and follow the propagation of the initial pulses. For linear perturbations we find single soliton solutions and solutions with one or more solitons followed by ""radiation"". Depending on the equation of state a strong damping may occur. We consider also the evolution of perturbations in a medium without dispersive effects. In this case we observe the formation and breaking of shock waves. We study all these equations also for matter at finite temperature. Our results may be relevant for the analysis of RHIC data. They suggest that the shock waves formed in the quark gluon plasma phase may survive and propagate in the hadronic phase. (C) 2009 Elseiver. B.V. All rights reserved.

Clustering and diffusion in a symplectic map lattice with non-local coupling

We study a symplectic chain with a non-local form of coupling by means of a standard map lattice where the interaction strength decreases with the lattice distance as a power-law, in Such a way that one can pass continuously from a local (nearest-neighbor) to a global (mean-field) type of coupling. We investigate the formation of map clusters, or spatially coherent structures generated by the system dynamics. Such clusters are found to be related to stickiness of chaotic phase-space trajectories near periodic island remnants, and also to the behavior of the diffusion coefficient. An approximate two-dimensional map is derived to explain some of the features of this connection. (C) 2008 Elsevier Ltd. All rights reserved.

Stochastic lattice gas model describing the dynamics of the SIRS epidemic process

We study a stochastic process describing the onset of spreading dynamics of an epidemic in a population composed of individuals of three classes: susceptible (S), infected (I), and recovered (R). The stochastic process is defined by local rules and involves the following cyclic process: S -> I -> R -> S (SIRS). The open process S -> I -> R (SIR) is studied as a particular case of the SIRS process. The epidemic process is analyzed at different levels of description: by a stochastic lattice gas model and by a birth and death process. By means of Monte Carlo simulations and dynamical mean-field approximations we show that the SIRS stochastic lattice gas model exhibit a line of critical points separating the two phases: an absorbing phase where the lattice is completely full of S individuals and an active phase where S, I and R individuals coexist, which may or may not present population cycles. The critical line, that corresponds to the onset of epidemic spreading, is shown to belong in the directed percolation universality class. By considering the birth and death process we analyze the role of noise in stabilizing the oscillations. (C) 2009 Elsevier B.V. All rights reserved.

An asymmetric sandpile model with height restriction

We analyze by numerical simulations and mean-field approximations an asymmetric version of the stochastic sandpile model with height restriction in one dimension. Each site can have at most two particles. Single particles are inactive and do not move. Two particles occupying the same site are active and may hop to neighboring sites following an asymmetric rule. Jumps to the right or to the left occur with distinct probabilities. In the active state, there will be a net current of particles to the right or to the left. We have found that the critical behavior related to the transition from the active to the absorbing state is distinct from the symmetrical case, making the asymmetry a relevant field.

Reversible and irreversible magnetization components behavior in Ni nanowires

Polycrystalline Ni nanowires were electrodeposited in nanoporous anodized alumina membranes with mean diameter of approximately 42 nm. Their magnetic properties were studied at 300 K, by measurements of recoil curves from demagnetized state and also from saturated state. M(rev) and M(irr) components were obtained and M(rev)(M(irr)) H curves were constructed from the experimental data. These curves showed a behavior that suggests a non-uniform reversal mode influenced by the presence of dipolar interactions in the system. A qualitative approach to this behavior is obtained using a Stoner-Wohlfarth model modified by a mean field term and local interaction fields. (C) 2008 Elsevier B.V. All rights reserved.

The effect of the negative coupling parameter on the spectrum of a trapped Bose gas

The interest in attractive Bose-Einstein Condensates arises due to the chemical instabilities generate when the number of trapped atoms is above a critical number. In this case, recombination process promotes the collapse of the cloud. This behavior is normally geometry dependent. Within the context of the mean field approximation, the system is described by the Gross-Pitaevskii equation. We have considered the attractive Bose-Einstein condensate, confined in a nonspherical trap, investigating numerically and analytically the solutions, using controlled perturbation and self-similar approximation methods. This approximation is valid in all interval of the negative coupling parameter allowing interpolation between weak-coupling and strong-coupling limits. When using the self-similar approximation methods, accurate analytical formulas were derived. These obtained expressions are discussed for several different traps and may contribute to the understanding of experimental observations.

Bose systems in spatially random or time-varying potentials

Bose systems, subject to the action of external random potentials, are considered. For describing the system properties, under the action of spatially random potentials of arbitrary strength, the stochastic mean-field approximation is employed. When the strength of disorder increases, the extended Bose-Einstein condensate fragments into spatially disconnected regions, forming a granular condensate. Increasing the strength of disorder even more transforms the granular condensate into the normal glass. The influence of time-dependent external potentials is also discussed. Fastly varying temporal potentials, to some extent, imitate the action of spatially random potentials. In particular, strong time-alternating potential can induce the appearance of a nonequilibrium granular condensate.

Role of Halogen Bonds in Thyroid Hormone Receptor Selectivity: Pharmacophore-Based 3D-QSSR Studies

Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TR alpha and TR beta. Several pharmacological effects mediated by TR beta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TR beta activation may elicit these effects while maintaining an acceptable safety profile, To understand the molecular determinants of affinity and subtype selectivity of TR ligands, we have successfully employed a ligand- and structure-guided pharmacophore-based approach to obtain the molecular alignment of a large series of thyromimetics. Statistically reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models were obtained using the comparative molecular field analysis (CoMFA) method, and the visual analyses of the contour maps drew attention to a number of possible opportunities for the development of analogs with improved affinity and selectivity. Furthermore, the 3D-QSSR analysis allowed the identification of a novel and previously unmentioned halogen bond, bringing new insights to the mechanism of activity and selectivity of thyromimetics.

Quantitative structure-activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: Molecular modeling, CoMFA and CoMSIA studies

Human parasitic diseases are the foremost threat to human health and welfare around the world. Trypanosomiasis is a very serious infectious disease against which the currently available drugs are limited and not effective. Therefore, there is an urgent need for new chemotherapeutic agents. One attractive drug target is the major cysteine protease from Trypanosoma cruzi, cruzain. In the present work, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted on a series of thiosemicarbazone and semicarbazone derivatives as inhibitors of cruzain. Molecular modeling studies were performed in order to identify the preferred binding mode of the inhibitors into the enzyme active site, and to generate structural alignments for the three-dimensional quantitative structure-activity relationship (3D QSAR) investigations. Statistically significant models were obtained (CoMFA. r(2) = 0.96 and q(2) = 0.78; CoMSIA, r(2) = 0.91 and q(2) = 0.73), indicating their predictive ability for untested compounds. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the information gathered from the 3D CoMFA and CoMSIA contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of cruzain inhibitors, and should be useful for the design of new structurally related analogs with improved potency. (C) 2009 Elsevier Inc. All rights reserved.

WRITING ELECTRONIC FERROMAGNETIC STATES IN A HIGH-TEMPERATURE PARAMAGNETIC NUCLEAR SPIN SYSTEM

In this paper, we use Nuclear Magnetic Resonance (NMR) to write electronic states of a ferromagnetic system into high-temperature paramagnetic nuclear spins. Through the control of phase and duration of radio frequency pulses, we set the NMR density matrix populations, and apply the technique of quantum state tomography to experimentally obtain the matrix elements of the system, from which we calculate the temperature dependence of magnetization for different magnetic fields. The effects of the variation of temperature and magnetic field over the populations can be mapped in the angles of spin rotations, carried out by the RF pulses. The experimental results are compared to the Brillouin functions of ferromagnetic ordered systems in the mean field approximation for two cases: the mean field is given by (i) B = B(0) + lambda M and (ii) B = B(0) + lambda M + lambda`M(3), where B(0) is the external magnetic field, and lambda, lambda` are mean field parameters. The first case exhibits second order transition, whereas the second case has first order transition with temperature hysteresis. The NMR simulations are in good agreement with the magnetic predictions.

Structure-Based Approach for the Study of Estrogen Receptor Binding Affinity and Subtype Selectivity

Estrogens exert important physiological effects through the modulation of two human estrogen receptor (hER) subtypes, alpa (hER alpha) and beta (hER beta). Because the levels and relative proportion of hER alpha and hER beta differ significantly in different target cells, selective hER ligands could target specific tissues or pathways regulated by one receptor subtype without affecting the other. To understand the structural and chemical basis by which small molecule modulators are able to discriminate between the two subtypes, we have applied three-dimensional target-based approaches employing a series of potent hER-ligands. Comparative molecular field analysis (CoMFA) studies were applied to a data set of 81 hER modulators, for which binding affinity values were collected for both hER alpha and hER beta. Significant statistical coefficients were obtained (hER alpha, q(2) = 0.76; hER beta, q(2) = 0.70), indicating the internal consistency of the models. The generated models were validated using external test sets, and the predicted values were in good agreement with the experimental results. Five hER crystal structures were used in GRID/PCA investigations to generate molecular interaction fields (MIF) maps. hER alpha and hER beta were separated using one factor. The resulting 3D information was integrated with the aim of revealing the most relevant structural features involved in hER subtype selectivity. The final QSAR and GRID/PCA models and the information gathered from 3D contour maps should be useful for the design or novel hER modulators with improved selectivity.

Three-dimensional quantitative structure-activity relationships for a large series of potent antitubercular agents

Comparative molecular field analysis (CoMFA) studies were conducted on a series of 100 isoniazid derivatives as anti-tuberculosis agents using two receptor-independent structural data set alignment strategies: (1) rigid-body fit, and (2) pharmacophore-based. Significant cross-validated correlation coefficients were obtained (CoMFA(1), q(2) = 0,75 and CoMFA(2), q(2) = 0.74), indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results.