Furanone derivatives as new inhibitors of CDC7 kinase: development of structure activity relationship model using 3D QSAR,molecular docking,and in silico ADMET

Cell division cycle 7 (CDC7) is a serine/threonine kinase, which plays a vital role in the replication initiation of DNA synthesis. Overexpression of the CDC7 in various tumor growths and in cell proliferation makes it a promising target for treatment of cancers. To investigate the binding between the CDC7 and furanone inhibitors, and in order to design highly potent inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) with molecular docking was performed. The optimum CoMSIA model showed significant statistical quality on all validation methods with a determination coefficient (R²?=?0.945), bootstrapping R² mean (BS-R²?=?0.960), and leave-one-out cross-validation (Q²) coefficient of 0.545. The predictability of this model was evaluated by external validation using a test set of nine compounds with a predicted determination coefficient R²_test of 0.96, besides the mean absolute error (MAE) of the test set was 0.258 log units. The extracted contour maps were used to identify the important regions, where the modification was necessary to design a new molecule with improved activity. Furthermore, a good consistency between the molecular docking and contour maps strongly demonstrates that the molecular modeling is reliable. Based on those obtained results, we designed several new potent CDC7 inhibitors, and their inhibitory activities were validated by the molecular models. Additionally, those newly designed inhibitors showed promising results in the preliminary in silico ADMET evaluations.     

Synthesis of Branched‐Chain Sugars with a DHAP‐Dependent Aldolase: Ketones are Electrophile Substrates of Rhamnulose‐1‐phosphate Aldolases

Dihydroxyacetone phosphate (DHAP)‐dependent rhamnulose aldolases display an unprecedented versatility for ketones as electrophile substrates. We selected and characterized a rhamnulose aldolase from Bacteroides thetaiotaomicron (RhuABthet) to provide a proof of concept. DHAP was added as a nucleophile to several α‐hydroxylated ketones used as electrophiles. This aldol addition was stereoselective and produced branched‐chain monosaccharide adducts with a tertiary alcohol moiety. Several aldols were readily obtained in good to excellent yields (from 76 to 95 %). These results contradict the general view that aldehydes are the only electrophile substrates for DHAP‐dependent aldolases and provide a new C?C bond‐forming enzyme for stereoselective synthesis of tertiary alcohols.     

Investigation of indirubin derivatives: a combination of 3D-QSAR,molecular docking,and ADMET towards the design of new DRAK2 inhibitors

Kinase-related apoptosis-inducing kinase 2 (DRAK2) is a serine/threonine kinase and belongs to the death-associated protein kinase DPAK family, which is responsible for induction of apoptosis in many cell types. Thus, DRAK2 is regarded as a promising target for treatment of autoimmune diseases. To investigate the binding between DRAK2 and indirubin inhibitors and design potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking were performed. Comparative Molecular Similarity Indices Analysis (CoMSIA) was developed using 33 molecules having pIC₅₀ ranging from 8.523 to 5.000 (IC₅₀ in nM). The best CoMSIA model gave a significant coefficient of determination (R²?=?0.93), as well as a (leave-one-out cross-validation coefficient Q² of 0.81. The predictive ability of this model was evaluated by external validation using a test set of eight compounds and yielded a predicted coefficient of determination R²_test of 0.94. The contour maps could provide structural features to improve inhibitory activity. Good consistency between contour maps and molecular docking strongly suggests that the molecular modeling is reliable. Based on these satisfactory results, we designed several new DRAK2 inhibitors and their inhibitory activities were predicted using different models, which are developed on different training and test sets. Additionally, these newly designed inhibitors showed promising results in the preliminary in silico ADMET evaluations compared to the best inhibitor from the studied dataset. This study could be useful in lead identification and optimization for early drug discovery of DRAK2 inhibitors.     

On Formal Modeling and Validation of Wireless Sensor Network Protocols

Formal verification is becoming more and more important in the field of wireless networks (WSN). The general purpose formal method called Event-B is the latest incarnation of the B Method: it is a proof based approach with a formal notation and refinement technique for modeling and verifying systems. Refinement enables implementation level features to be proven correct with respect to an abstract specification of the system. This paper proposes an initial attempt to model and verify consistency and correctness of a WSN operation in its different layers. Several formal models are introduced for this type of networks. In the first time, coloured Petri net are used to elaborate network layer models, then each one will be detailed by an Event-B formalism, while proofs are carried out using the RODIN platform which is an integrated development framework for Event-B.

     

Conformation study of poly(p‐dioxanone) fibers by polarized Raman spectroscopy,X‐ray diffraction,and conformation analysis

The molecular orientation distribution of poly(p‐dioxanone) (PPDX) uniaxially oriented commercial fibers was determined by polarized Raman spectroscopy and X‐ray diffraction. The order parameters 〈P₂₀₀〉 and 〈P₄₀₀〉 of the orientation distribution function were determined by polarized Raman spectroscopy. For the C?O stretching band, the values of 〈P₂₀₀〉 and 〈P₄₀₀〉 obtained are equal to ?0.40 ± 0.04 and 0.28 ± 0.04, respectively. These results clearly indicate that the carbonyl groups are highly oriented perpendicular to the fiber axis. X‐ray diffraction led to a fiber repeat value of 0.628 nm for these samples, and to 〈P₂₀₀〉 and 〈P₄₀₀〉 values of 0.93 and 0.82, respectively, for the c‐axis orientation, indicating a high orientation in the draw direction of the fibers. A Monte‐Carlo conformational search led to 20 low‐energy conformations, but only one of these was found compatible with both the fiber repeat and the angle between the C?O bond and the fiber axis. This conformation, a 2₁ helix with a tg^?ttg^? succession of torsion angles, is proposed as the existing conformation in the crystalline state. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 406–417, 2008     

Structural characterisation of CdS layers deposited on porous p-type GaAs

The purpose of this paper is to investigate the initial stage of cadmium sulphide (CdS) layer deposited on porous p-type GaAs substrate by vacuum evaporation technique. The deposited CdS layer was investigated by scanning electron microscopy (SEM), atomic force microscopy (AFM) and X-ray diffraction (XRD). SEM imaging shows that the CdS was penetrated deeply in the porous structure down to the bottom and reaching the interface GaAs/porous GaAs. The AFM image demonstrates that the CdS deposited are grains of several nanometres and XRD patterns exhibit that the deposited layer has a hexagonal prominent phase.     

Simulation théorique et expérimentale du fonctionnement d’un banc de mesure à structure triaxiale appliquée à la mesure de l’impédance de transfert des câbles multifilaires blindés

We are interested in the present paper in the measure of the transfer impedance and the near-end crosstalk voltages of multi-wire shielded cable by applying the well-known transmission-line theory. Using the impedance and admittance transfer measurement set up, we show that conductors inside the shield play an important role in the evaluation of the internal voltages. We equally show that when the conduction coupling appear, we can not neglect the reaction of the interior wires with regard to the exterior.     

Routing and Wavelength Assignment in Multi-Segment WDM Optical Networks using Clustering Techniques

This paper studies the routing and wavelength assignment (RWA) problem in multi-segment optical networks. The notion of network segment is referred to any part of the network that requires special consideration of wavelength routing such as separate administrative domains in a large scale optical network, sub-networks run by various service providers, etc. In multi-segment optical networks, each segment has different resource availability or hardware characteristics. The differences between multi-segment optical networks and homogeneous optical networks are discussed. We then present a resource abstraction technique called blocking island and define a multi-segment blocking island graph (BIG) network model. Using a minimum splitting routing heuristic introduced in the context of the blocking island paradigm in conjunction with the multi-segment BIG model, we propose a general RWA algorithm that takes a combined view of the network resource to integrate routing, wavelength assignment and gateway selection in a single routing framework. In the simulation, we demonstrate the effectiveness of our proposed algorithm by comparing it with other state-of-the-art heuristics in this area.     

A unified framework for performance evaluation over generalized fading channels

In this paper, we present a unified framework to analyze the performance of the average bit error probability (BEP) and the outage probability over generalized fading channels. Specifically, we assume that the probability density function (PDF) of the instantaneous signal-to-noise ratio \(\zeta \) is given by the product of: power function, exponential function, and the modified Bessel function of the first kind, i.e., \(f_{\zeta }(\zeta )=\zeta ^{\lambda -1}exp\left( -a\zeta ^{\beta }\right) I_{v}\left( b\zeta ^{\beta }\right) \). Based on this PDF, we obtain a novel closed-form expression for the average BEP over such channels perturbed by an additive white generalized Gaussian noise (AWGGN). Note that other well-known noise types can be deduced from the AWGGN as special cases such as Gaussian noise, Laplacian noise, and impulsive noise. Furthermore, we obtain a novel closed-form expression for the outage probability. As an example of such channels, and without loss of generality, we analyze the performance of the average BEP and the outage probability over the \(\eta \)–\(\mu \) fading channels. Analytical results accompanied with Monte-Carlo simulations are provided to validate our analysis.     

Hybrid QoS based routing protocol for inter and intra wireless mesh infrastructure communications

Quality of service (QoS) in wireless mesh networks is an active area of research, which is driven by the increasing demand for real-time and multimedia applications, such as Voice over IP and Video on Demand. In this paper, we propose a novel QoS based routing protocol for wireless mesh infrastructure, called Hybrid QoS Mesh Routing (HQMR). It is composed of two QoS based routing sub-protocols: a reactive multi-metric routing protocol for intra-infrastructure communications and a proactive multi-tree based routing protocol for communications with external networks. The proposed routing protocol enables forwarding real-time and streaming applications with QoS guarantee in a mesh wireless environment, by assigning a specific routing path for each defined service class. To this end, three different QoS service classes are defined, depending on the applications requirements. We analyze in this paper the simulation results of different scenarios conducted on the network simulator ns-3 to demonstrate the effectiveness of the HQMR protocol and to compare it to other routing protocols while forwarding real-time applications with QoS guarantee.