Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer. Predominantly, AGR2 exists as a homodimer via a dimerization domain (E60-K64); after it is self-dimerized, it helps FGF2 and VEGF to homo-dimerize and promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts. Up till now, no small molecule has been discovered to inhibit the AGR2–AGR2 homodimer. Therefore, the present study was performed to prepare a validated 3D structure of AGR2 by homology modeling and discover a small molecule by screening the FDA-approved drugs library on AGR2 homodimer as a target protein. Thirteen different homology models of AGR2 were generated based on different templates which were narrowed down to 5 quality models sorted by their overall Z-scores. The top homology model based on PDB ID?=?3PH9 was selected having the best Z-score and was further assessed by Verify-3D, ERRAT and RAMPAGE analysis. Structure-based virtual screening narrowed down the large library of FDA-approved drugs to ten potential AGR2–AGR2 homodimer inhibitors having FRED score lower than ? 7.8 kcal/mol in which the top 5 drugs’ binding stability was counter-validated by molecular dynamic simulation. To sum up, the present study prepared a validated 3D structure of AGR2 and, for the first time reported the discovery of 5 FDA-approved drugs to inhibit AGR2–AGR2 homodimer by using structure-based virtual screening. Moreover, the binding of the top 5 hits with AGR2 was also validated by molecular dynamic simulation.

Graphic abstract

A validated 3D structure of Anterior Gradient 2 (AGR2) was prepared by homology modeling, which was used in virtual screening of FDA-approved drugs library for the discovery of prospective inhibitors of AGR2–AGR2 homodimer.

     

Discovery of inhibitors targeting protein tyrosine phosphatase 1B using a combined virtual screening approach

Molecular Diversity - Protein tyrosine phosphatase 1B (PTP1B) acts as a therapeutic target for type 2 diabetes. However, the major challenges of PTP1B drug discovery are the poor selectivity and...     

Multiscale modeling of alloy solidification using a database approach

A two-scale model based on a database approach is presented to investigate alloy solidification. Appropriate assumptions are introduced to describe the behavior of macroscopic temperature, macroscopic concentration, liquid volume fraction and microstructure features. These assumptions lead to a macroscale model with two unknown functions: liquid volume fraction and microstructure features. These functions are computed using information from microscale solutions of selected problems. This work addresses the selection of sample problems relevant to the interested problem and the utilization of data from the microscale solution of the selected sample problems. A computationally efficient model, which is different from the microscale and macroscale models, is utilized to find relevant sample problems. In this work, the computationally efficient model is a sharp interface solidification model of a pure material. Similarities between the sample problems and the problem of interest are explored by assuming that the liquid volume fraction and microstructure features are functions of solution features extracted from the solution of the computationally efficient model. The solution features of the computationally efficient model are selected as the interface velocity and thermal gradient in the liquid at the time the sharp solid–liquid interface passes through. An analytical solution of the computationally efficient model is utilized to select sample problems relevant to solution features obtained at any location of the domain of the problem of interest. The microscale solution of selected sample problems is then utilized to evaluate the two unknown functions (liquid volume fraction and microstructure features) in the macroscale model. The temperature solution of the macroscale model is further used to improve the estimation of the liquid volume fraction and microstructure features. Interpolation is utilized in the feature space to greatly reduce the number of required sample problems. The efficiency of the proposed multiscale framework is demonstrated with numerical examples that consider a large number of crystals. A computationally intensive fully-resolved microscale analysis is also performed to evaluate the accuracy of the multiscale framework.     

Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening approach

Molecular Diversity - The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the...     

Modeling of high-frequency scattering from objects using a hybrid Kirchhoff/diffraction approach

In this paper a numerical discretization and transformation into the time domain of a hybrid Kirchhoff/diffraction method is presented for the modeling of high-frequency pulse scattering from rigid bodies. A series of benchmark cases, for smooth and rough spheres and cylinders, is presented to establish the accuracy of the method in the time domain.     

Investigation of multicomponent diffusion in cat brain using a combined MTC-DWI approach

In this study, multiple-component water diffusion in the cat brain is investigated using an approach that combines diffusion-weighted images using multiple b values with magnetization transfer contrast (MTC). The MTC allows filter of signal originating from water molecules that rapidly exchange with binding sites on large macromolecular structures, and in brain white matter, it is assumed that a significant portion of the MTC is due to the interaction of water with the extraaxonal myelin sheath. Henceforth, multicomponent analysis of diffusion curves with and without MTC may shed light on the contribution of the extraaxonal water to the diffusion signal and on the relationship between diffusion components and tissue compartments in the brain. When a biexponential model was applied to the data, the volume fractions of the two diffusion components changed significantly in white matter with the application of the MTC. These changes are then discussed in the frame of tissue components and the possible interaction with the myelin sheath.     

Measurement of APT using a combined CERT-AREX approach with varying duty cycles

The goal is to develop an imaging method where contrast reflects amide-water magnetization exchange, with minimal signal contributions from other sources. Conventional chemical exchange saturation transfer (CEST) imaging of amides (often called amide proton transfer, or APT, and quantified by the metric MTR_asym) is confounded by several factors unrelated to amides, such as aliphatic protons, water relaxation, and macromolecular magnetization transfer. In this work, we examined the effects of combining our previous chemical exchange rotation (CERT) approach with the non-linear AREX method while using different duty cycles (DC) for the label and reference scans. The dependencies of this approach, named AREX_double,vdc, on tissue parameters, including T₁, T₂, semi-solid component concentration (f_m), relayed nuclear Overhauser enhancement (rNOE), and nearby amines, were studied through numerical simulations and control sample experiments at 9.4 T and 1 μT irradiation. Simulations and experiments show that AREX_double,vdc is sensitive to amide-water exchange effects, but is relatively insensitive to T₁, T₂, f_m, nearby amine, and distant aliphatic protons, while the conventional metric MTR_asym, as well as several other APT imaging methods, are significantly affected by at least some of these confounding factors.     

Identifying potential inhibitors of biofilm-antagonistic proteins to promote biofilm formation: a virtual screening and molecular dynamics simulations approach

Molecular Diversity - Microbial biofilms play a critical role in environmental biotechnology and associated applications. Biofilm production can be enhanced by inhibiting the function of proteins...     

Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach

JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 ( $Q_{\mathrm{test}}^{2} 0.663, R^{2}_{\mathrm{train}} 0.849$ , F value 219.3) for JAK2 and ADDRR.142 ( $Q^{2}_{\mathrm{test}}0.655, R_{\mathrm{train}}^{2}$ 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.     

Identification of organic molecules from a structure database using proton and carbon NMR analysis results

A compound is identified by matching its proton and/or carbon NMR spectra to NIH PubChem molecular structures. The matching process involves analyzing 1D proton, 1D carbon, DEPT, and/or HSQC spectra, and comparing the number of NMR resonances, detected proton and carbon shifts, likely number of methyl- and methoxy-groups, and an optionally specified molecular formula to predicted proton and carbon shifts of PubChem structures. A structure verification module rates the consistency between experimental spectral analysis results and a proposed structure (not limited to PubChem structures) and assigns observed shifts to the proposed structure. The spectral analysis, structure identification, and structure verification are largely automated in a software package and can be performed in minutes.     

Fidelity of three-dimensional-sound reproduction using a virtual auditory display

The fidelity of reproducing free-field sounds using a virtual auditory display was investigated in two experiments. In the first experiment, listeners directly compared stimuli from an actual loudspeaker in the free field with those from small headphones placed in front of the ears. Headphone stimuli were filtered using head-related transfer functions (HRTFs), recorded while listeners were wearing the headphones, in order to reproduce the pressure signatures of the free-field sounds at the eardrum. Discriminability was investigated for six sound-source positions using broadband noise as a stimulus. The results show that the acoustic percepts of real and virtual sounds were identical. In the second experiment, discrimination between virtual sounds generated with measured and interpolated HRTFs was investigated. Interpolation was performed using HRTFs measured for loudspeaker positions with different spatial resolutions. Broadband noise bursts with flat and scrambled spectra were used as stimuli. The results indicate that, for a spatial resolution of about 6 degrees, the interpolation does not introduce audible cues. For resolutions of 20 degrees or more, the interpolation introduces audible cues related to timbre and position. For intermediate resolutions (10 degrees - 15 degrees) the data suggest that only timbre cues were used.     

Fully-automated approach to hippocampus segmentation using a graph-cuts algorithm combined with atlas-based segmentation and morphological opening

The hippocampus has been known to be an important structure as a biomarker for Alzheimer’s disease (AD) and other neurological and psychiatric diseases. However, it requires accurate, robust and reproducible delineation of hippocampal structures. In this study, an automated hippocampal segmentation method based on a graph-cuts algorithm combined with atlas-based segmentation and morphological opening was proposed. First of all, the atlas-based segmentation was applied to define initial hippocampal region for a priori information on graph-cuts. The definition of initial seeds was further elaborated by incorporating estimation of partial volume probabilities at each voxel. Finally, morphological opening was applied to reduce false positive of the result processed by graph-cuts. In the experiments with twenty-seven healthy normal subjects, the proposed method showed more reliable results (similarity index = 0.81 ± 0.03) than the conventional atlas-based segmentation method (0.72 ± 0.04). Also as for segmentation accuracy which is measured in terms of the ratios of false positive and false negative, the proposed method (precision = 0.76 ± 0.04, recall = 0.86 ± 0.05) produced lower ratios than the conventional methods (0.73 ± 0.05, 0.72 ± 0.06) demonstrating its plausibility for accurate, robust and reliable segmentation of hippocampus.     

Scattering in a Pekeris waveguide from a rough bottom using a two-way coupled mode approach

Scattering from a rough ocean bottom is described numerically with a two-way coupled-mode formalism that contains scattering effects to all orders and provides an exact solution to the wave equation. Both scattered field and direct blast components are computed within the formalism framework. A comparison of the scattered component solution from the coupled mode with the Born approximation (BA) solution for scattering from a rough bottom Pekeris waveguide shows that the BA predicts correctly the scattered field levels but not detailed structure. The transition from direct blast to scattered field dominance is identified in the total field time series.     

Suppression of maglev vehicle-girder self-excited vibration using a virtual tuned mass damper

The self-excited vibration that occurs between a stationary Electromagnetic Suspension (EMS) maglev vehicle and a girder is a practical problem that greatly degrades the performance of a maglev system. As of today, this problem has not been fully solved. In this article, the principle underlying the self-excited vibration problem is explored, and it is found that the fundamental resonance frequency of the maglev girder plays a vital role in the initiation of the self-excited vibration. To suppress the self-excited vibration, a scheme applying a tuned mass damper (TMD) to the maglev girder is proposed, and the stability of the combined system is analyzed. Furthermore, a novel concept of a virtual TMD is introduced, which uses an electromagnetic force to emulate the force of a real TMD acting on the girder. However, in the presence of the time delay caused by the inductance of the electromagnets, the stability analysis of the levitation system combined with the virtual TMD becomes complex. Analysis of the stability shows that there exist some repeated time delay zones within which the overall system is stable. Based on this rule, time delay control is introduced to stabilize the system with a virtual TMD, and a procedure to determine the optimal time delay and gain is proposed. Numerical simulation indicates that the proposed virtual TMD scheme can significantly suppress the self-excited vibration caused by one unstable vibration mode, and is suitable for application to EMS maglev systems.     

On the externalization of virtual sound images in headphone reproduction: a Wiener filter approach

In-head localization of sound images is a critical problem in headphone reproduction. The paper investigates the degree of externalization in terms of the distance of auditory images for various synthesis and reproduction cases. An effective binaural headphone system was constructed by way of binaural synthesis using head-related impulse responses and individual headphone equalization using Wiener filter theory. The headphone system designed had an average reproduction performance error of 2.4% for five subjects with a random noise input, and was used to perform some subjective tests with a set of virtual sources equally spaced and distanced from the center of each subject's head in the horizontal plane. The effects of individual and nonindividual binaural syntheses and those of equalized and nonequalized reproductions were separately investigated. In the tests, each subject was instructed to indicate the distance of auditory images. The results obtained demonstrate that individual equalization is important for externalization, and individual synthesis is important for consistent distance perception. Thus, a combined use of both individual equalization and individual synthesis resulted in externalized sound images of a consistent distance.     

Enhanced growth of low-resistivity cobalt silicide by using a Co/Au/Co trilayer film on Si0.8Ge0.2 virtual substrate

Formation of Co germanosilicides on Si_0.8Ge_0.2 virtual substrates with a Co/Au/Co sandwich thin film after different heat treatments has been investigated. The sequence of phase formation is the same as the reaction of blanket Co thin film with (001)Si. The presence of thin interposing Au layers was found to significantly enhance the formation of low-resistivity CoSi₂ on (001)Si_0.8Ge_0.2 substrates. The formation temperature of CoSi₂ phase in the Co/Au/Co/(001)Si_0.8Ge_0.2 samples was lowered by about 200 °C compared to that of Co/(001)Si_0.8Ge_0.2 samples. From TEM and EDS analysis, some of Au atoms were found to diffuse from the original interface position to disperse within the CoSi₂ layers during silicidation reactions. The mechanisms for the enhanced formation of CoSi₂ in the Co/Au/Co/Si_0.8Ge_0.2 system were explained in the context of classical nucleation theory.     

消声器传递损失预测的边界元模态展开混合方法

将边界元法和解析方法结合形成一种混合方法用于计算消声器的传递损失,消声器被划分成若干个子结构,解析方法和边界元方法被分别用于计算规则结构和不规则结构的阻抗矩阵,不同子结构之间通过阻抗矩阵连接起来。为减少计算时间,采用一种基于模态配点法的简化方法。对单级膨胀腔、双级膨胀腔和穿孔管阻性消声器的传递损失进行了计算,混合方法计算结果与解析方法和三维数值方法计算结果吻合良好。分析了混合方法的计算效率并与传统子结构方法进行了比较,混合方法能明显节省计算时间。