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.     

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.     

Optical,structural, and photoelectrochemical properties of nanostructured ln-doped ZnO via electrodepositing method

Indium-doped zinc oxide nanorods were electrochemically deposited at low temperature on ITO substrates. The synthesized ZnO-arrayed layers were investigated by using X-ray diffraction, scanning electron microscopy, UV–vis transmittance, electrochemical impedance spectroscopy, and photocurrent spectroscopy. X-ray diffraction analysis demonstrates that the electrodeposited films are crystalline and present the hexagonal Würtzite ZnO phase with preferential (002) orientation. The ZnO films obtained forms aligned hexagonal nanorods, and depending on the increasing In concentration, the surface morphologies of the films are changed. The ln-doped ZnO nanorods (NRs) are well-aligned with the c-axis being perpendicular to the substrates when the ln concentration was between 0 and 2 at.%. of In, the grown films with In contents up to 4 at.%, changes in the optical band gap from 3.31 to 3.39 eV, and the blue shift in the band gap energy was attributed to the Burstein–Moss effect. The effect of In concentration on the photocurrent generated by films shows that the obtained thin films can be used as a photovoltaic material. Changes in the photocurrent response and the electronic disorder were also discussed in the light of In doping. It was found that the carrier density of IZO thin films varied between 1.06?×?10¹⁸ and 1.88?×?10¹⁸ cm^?3 when the In concentration was between 0 and 4 at.%.

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Graphical Abstract Photocurrent response of IZO samples

     

An additional projection step to He and Liao's method for solving variational inequalities

In this paper, we proposed a modified extragradient method for solving variational inequalities. The method can be viewed as an extension of the method proposed by He and Liao [Improvement of some projection methods for monotone variational inequalities, J. Optim. Theory Appl. 112 (2002) 111–128], by performing an additional projection step at each iteration and another optimal step length is employed to reach substantial progress in each iteration. We used a self-adaptive technique to adjust parameter ρ$\rho$ at each iteration. Under certain conditions, the global convergence of the proposed method is proved. Preliminary numerical experiments are included to compare our method with some known methods.     

An inexact implicit method for general mixed variational inequalities

In the present paper, we present an inexact implicit method with a variable parameter for general mixed variational inequalities. We use a self-adaptive technique to adjust parameter ρ$\rho$ at each iteration. The main advantage of this technique is that the method can adjust the parameter automatically and the numbers of iteration are not very sensitive to different initial parameter _ρ0.${\rho }_0.$     

A reversible metal-ligand bond break associated to a spin-crossover

The [Fe(II)L(CN)(2)].H(2)O complex, dicyano[2,13-dimethyl-6,9-dioxa-3,12,18-triazabicyclo[12.3.1]octadeca-1(18),2,12,14,16-pentaene]iron(II) monohydrate, exhibits a thermal induced metal-ligand bond break reversible in the solid state and associated to a spin crossover that corresponds to an unprecedented structurally characterized modification of the coordination metal environment from a hepta-coordinate high spin state to a hexa-coordinate low spin state.     

Numerical analysis of the effect of the gas temperature on splat formation during thermal spray process

Thermal spray coatings are affected by various parameters. In this study, the finite element method with volume of fluid (VOF) procedure is used to investigate the deposition process which is very important for the quality of sprayed coatings. The specific heat method (SHM) is used for the solidification phenomenon. A comparison of the present model with experimental and numerical model available in the literature is done. A series of numerical calculations is carried out to investigate the effect of the surrounding gas temperature on the splat formation. The variation of the surrounding gas temperature has a significant effect on splat morphology and can affect the adhesion of the splat on the substrate.     

Modified descent-projection method for solving variational inequalities

In this paper, we propose a modified descent-projection method for solving variational inequalities. The method makes use of a descent direction to produce the new iterate and can be viewed as an improvement of the descent-projection method by using a new step size. Under certain conditions, the global convergence of the proposed method is proved. In order to demonstrate the efficiency of the proposed method, we provide numerical results for a traffic equilibrium problems.     

The effect of thiourea as a complexing agent on the separation of metallic ions through cation exchange membranes by Donnan dialysis

Donnan dialysis has been investigated in this work in the order to exhibit the influence of the composition of solution on the performance of commercial cation exchange membrane toward metallic ions. Transference fluxes have been determined either as experimental values or calculated according to theoretical models. A good agreement between theoretical and experimental flows has been obtained principally in the case of CMV membrane which presents a lower thickness. It has been demonstrated that addition of thiourea causes an increase of separation properties of membrane. The separation is mainly due to the complex formation between Ag⁺ and Cu⁺ ions and thiourea. Monovalent copper ion is obtained after reduction of Cu²⁺ and oxidation of thiourea and formation of bisulfide of formamidine which constitute a barrier to monovalent complex transference.     

New inexact implicit method for general mixed quasi variational inequalities

In this paper, we suggest and analyze a new self-adaptive inexact implicit method with a variable parameter for general mixed quasi variational inequalities, where the skew-symmetry of the nonlinear bifunction plays a crucial part in the convergence analysis of this method. We use a self-adaptive technique to adjust parameter ρ at each iteration. The global convergence of the proposed method is proved under some mild conditions. Preliminary numerical results indicate that the self-adaptive adjustment rule is necessary in practice. Muhammad Aslam Noor is supported by the Higher Education Commission, Pakistan, through research grant No: 1-28/HEC/HRD/2005/90.