Identification of novel PI3Kδ inhibitors by docking,ADMET prediction and molecular dynamics simulations

BackgroundPhosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects.MethodComputer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor.ResultsBased on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: −12.175 kcal/mol, cdocker binding energy: −42.975 kcal/mol and ΔG_bind value: −90.457 kcal/mol) and BAS 00227397 (Glide score: −10.988 kcal/mol, cdocker binding energy: −39.3376 kcal/mol and ΔG_bind value: −81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand’s behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket.ConclusionCompound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.     

Frequencies Rotation at High Sound Pressure Levels Toward Low Frequencies

Today, analyzing of sound pressure level and frequency is considered as an important index in human society. Sound experts believe that analyzing of these parameters can help us to better understanding of work environments. Sound measurements and frequency analysis did to fix the harmful frequency in all sections in Shiraz gas power plant with sound analyzer model BSWA 308. The sound pressure levels (L_P) and the one and one-third octave band were continuously measured in A and C weighting networks and slow mode for time response. Excel 2013 and Minitab 18.1 software used for statistical calculations. Results analyzed by Minitab 18.1 software. The highest harmful frequency in Shiraz Gas Power Plant (SGPP) was 50 Hz with 115 dB. The sound pressure level (SPL) ranged from 45 dB to 120 dB in one-third octave band and weighting network C. The maximum sound pressure level was in Craft electricity generator with 105.3 dB and 67 Hz. Sound pressure level in surrounded environment was 120 dB. According to the results, in this industry the sound pressure level exceeded the Occupational Exposure Level of Iran (OEL). The value of sound pressure level were higher than the Standard of occupational health. SGPP consumes 47000 cubic meters of natural gas per hour to produce 100 MW (Mega Watt) of electricity. It is very high and it is not economical and cost effective. These numbers indicate that the power plant’s efficiency is low. It could be concluded that the noise pollution is an important issue in these industries. Moreover, SGPP produce noise with loss energy. Frequencies rotation at high sound pressure levels toward low frequencies were happened.     

Enhancement of pupil-masked wavelength-scale gas-filled flat acoustic lens based on anomaly apodization effect

In this letter, the improvement in focus by the use of a pupil mask produced in an acoustic mesoscale cuboid particle filled with CO₂ is reported. Thereby, the result shows that the pupil mask increases the sound intensity and also increases the resolution (or a reduction of the full width at half maximum, FWHM) in focus compared to the non-masked one. These results are important because they confirm the effect of abnormal amplitude apodization for a one-wavelength dimension acoustic lens and demonstrate that it is possible to improve sound focusing of a cuboid gas-filled lens with one wavelength dimension. This is the smallest size of an acoustic lens ever considered in this type of literature, with side dimensions of the cube equal to one wavelength and a diameter to focus ratio of 2.5, the sound amplification in focus is 5.4 dB at 4125 Hz, with the resolution near to the diffraction limit.     

Using a virtual skeleton to increase printability of topology optimized design for industry-class applications

This article broadens the scheme previously developed to associate topology optimization with additive manufacturing through the use of a virtual skeleton, consisting in solving the same physical problem with a discrete approach and then with a continuum one. This procedure for 3D designs is applied to various domain geometries, to demonstrate its pertinence on high-resolution industrial cases. An algorithm searching for the best printing direction, exploring the solid angle, is also described and validated; the surface-shaped presentation of the result allows immediate understanding of the influence of the discrete problem parameters, while its running time is much lower than a unique continuum optimization simulation, which proves the attractiveness of the method. In the three examples studied, the procedure outputs exhibit greater printability than the ones produced by traditional methods in each of the printing direction tested, albeit responsibility is left to the final user to choose his best trade-off. Furthermore, the unprintable zones are readily displayed to be either reworked or supported. Explanations about increase of convergence likelihood on discrete structures despite the geometry complexity of an industrial application are also provided and demonstrated.     

利用混合FE-SEA方法的前围隔声性能优化设计*

为了提升某重型商用车前围的隔声性能,建立了用于分析前围传递损失的有限元-统计能量分析(FE-SEA)模型。针对前围结构复杂的特点,依据FE-SEA模型建模原则,提出了通过在表面创建声腔来确保能量在模型中的正确传递路径。将仿真结果与测试值对比,二者误差小于1.6 dB(A),验证了FE-SEA方法的准确性。用吸声材料与隔声材料复合设计前围声学包,采用正交试验法对前围声学包进行优化设计并对各个试验方案进行仿真计算。对仿真结果进行极差分析与方差分析,选出了在传递损失、重量和厚度三方面达到最佳平衡的声学包:毛毡(10 mm)+EPDM隔声垫(2 mm)。结果表明,优化后的前围传递损失在测试频率315 Hz～2000 Hz范围内最小提升了3.8 dB(A),最大提升了7 dB(A),前围的隔声性能得到较大的提升。     

The (S−1,S) inventory model and its counterparts in queueing theory

We explore the relationship between the ($S?1,S$) inventory model and three well-known queueing models: the Erlang loss system, the machine-repair model and a two-node Jackson network. Exploiting this relationship allows us to obtain key performance measures of the ($S?1,S$) model, like the so-called virtual outdating time, the number of items on the shelf in steady state, the long-run rate of unsatisfied demands and the distribution of the empty shelf period.     

膨胀腔类超材料的传递损失研究*

声学超材料及结构已被广泛研究，其超结构通常利用3D打印技术实现，当结构刚度较小或者面积较大时，由声固耦合所导致的声学效果与设计不符的情况广泛存在。本文针对含有膨胀腔类的超材料，研究了声固耦合对其声学性能的影响，采用有限元计算结合阻抗管实验的方法，得到其传递损失，分析了声固耦合现象对传递损失的影响。结果表明：薄壁膨胀腔结构的作用频率范围与只考虑声学理论计算的设计不符，声固耦合现象对传递损失产生显著影响；采用增加膨胀腔壁厚、减少膨胀腔内径或选择金属材料的方式，都可以使得声固耦合现象对传递损失的影响减小；仿真结果与实验结果基本吻合。该研究结果说明：对于膨胀腔类超材料，当刚度较小或者面积较大时，对其进行声固耦合分析是完全必要的。     

基于深度约束的声速估算方法*

高精度的声速剖面数据是提高水下定位精度的关键。在无法精确获得声速剖面数据的情况下，该文提出了一种基于深度约束，同时根据浮标与水下目标的空间几何距离进行有效声速估算的方法。通过仿真模拟，将该文提出的方法与加权平均声速法、泰勒级数展开法和等效声速剖面法的定位结果进行对比分析。结果表明，新方法不需要依靠声速剖面数据，通过深度约束可有效地估算出声速值，其定位精度与等效声速结果相当，极大地提高了无声速剖面数据下的水下定位精度。     

Similar,or dissimilar,that is the question. How different are methods for comparison of compounds similarity?

Comparison of compounds similarity is one of the main strategies of virtual screening protocols. Both similarity and dissimilarity concepts are of great importance during the search for new active compounds. Similarity is important due to the assumption that underlies the process of searching for new drug candidates: structurally similar compounds should induce similar biological response. On the other hand, we are also interested in dissimilarity, as we usually aim to find structurally novel ligands. In the study, we compared several approaches of evaluating compound similarity. Various representations and metrics were applied and we indicated the rate of variation of the results that can occur when shifting from one strategy to another. We compared both general similarity of datasets using different approaches, as well as examined the changes in the set of nearest neighbors when changing one compound representation into another, and the influence of representation/metric settings on the clustering outcome. We hope that the study will be of great help during the preparation of virtual screening experiments, stressing the need for careful selection of the way, the compound similarity is assessed. The differences in the results that can be obtained via the application of particular strategy can significantly influence the outcome of comparison studies; therefore, its settings should be carefully selected beforerunning the comparison.