AKT Inhibitors: The Road Ahead to Computational Modeling-Guided Discovery

AKT, is a serine/threonine protein kinase comprising three isoforms—namely: AKT1, AKT2 and AKT3, whose inhibitors have been recognized as promising therapeutic targets for various human disorders, especially cancer. In this work, we report a systematic evaluation of multi-target Quantitative Structure-Activity Relationship (mt-QSAR) models to probe AKT’ inhibitory activity, based on different feature selection algorithms and machine learning tools. The best predictive linear and non-linear mt-QSAR models were found by the genetic algorithm-based linear discriminant analysis (GA-LDA) and gradient boosting (Xgboost) techniques, respectively, using a dataset containing 5523 inhibitors of the AKT isoforms assayed under various experimental conditions. The linear model highlighted the key structural attributes responsible for higher inhibitory activity whereas the non-linear model displayed an overall accuracy higher than 90%. Both these predictive models, generated through internal and external validation methods, were then used for screening the Asinex kinase inhibitor library to identify the most potential virtual hits as pan-AKT inhibitors. The virtual hits identified were then filtered by stepwise analyses based on reverse pharmacophore-mapping based prediction. Finally, results of molecular dynamics simulations were used to estimate the theoretical binding affinity of the selected virtual hits towards the three isoforms of enzyme AKT. Our computational findings thus provide important guidelines to facilitate the discovery of novel AKT inhibitors.     

Molecular Dynamics Simulations Based on 1-Phenyl-4-Benzoyl-1-Hydro-Triazole ERRα Inverse Agonists

Estrogen-related receptor α (ERRα), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERRα inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERRα. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.     

Dynamic “Molecular Portraits” of Biomembranes Drawn by Their Lateral Nanoscale Inhomogeneities

To date, it has been reliably shown that the lipid bilayer/water interface can be thoroughly characterized by a sophisticated so-called “dynamic molecular portrait”. The latter reflects a combination of time-dependent surface distributions of various physicochemical properties, inherent in both model lipid bilayers and natural multi-component cell membranes. One of the most important features of biomembranes is their mosaicity, which is expressed in the constant presence of lateral inhomogeneities, the sizes and lifetimes of which vary in a wide range—from 1 to 10³ nm and from 0.1 ns to milliseconds. In addition to the relatively well-studied macroscopic domains (so-called “rafts”), the analysis of micro- and nanoclusters (or domains) that form an instantaneous picture of the distribution of structural, dynamic, hydrophobic, electrical, etc., properties at the membrane-water interface is attracting increasing interest. This is because such nanodomains (NDs) have been proven to be crucial for the proper membrane functioning in cells. Therefore, an understanding with atomistic details the phenomena associated with NDs is required. The present mini-review describes the recent results of experimental and in silico studies of spontaneously formed NDs in lipid membranes. The main attention is paid to the methods of ND detection, characterization of their spatiotemporal parameters, the elucidation of the molecular mechanisms of their formation. Biological role of NDs in cell membranes is briefly discussed. Understanding such effects creates the basis for rational design of new prospective drugs, therapeutic approaches, and artificial membrane materials with specified properties.     

EFFECTS OF SPECIFIED BLANK SIZE ON BODY WRINKLING DURING HYDRODYNAMIC DEEP DRAWING OF TAPERED RECTANGULAR BOX

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Trickle Flow Multiplicity: The Influence of the Prewetting Procedure on Flow Hysteresis

The existence of multiple hydrodynamic studies (MHS) in trickle flow is a well-known phenomenon. It is also known that different prewetting procedures result in major differences in MHS when the hydrodynamic variables pressure drop, liquid holdup and gas–liquid mass transfer are considered. Given a certain prewetting procedure one still has the option to perform flow hysteresis cycles to achieve an even wider variety of MHS. Although numerous studies have been performed on trickle flow hysteresis, none have attempted to decouple the hysteresis behaviour from the prewetting procedure followed. Accordingly there are numerous hysteresis possibilities that have not been investigated. In this work a single liquid and gas cycle were performed for four distinct prewetting procedures described here as a dry bed, a Levec type prewetted bed, Kan prewetted bed (achieved by increasing either the liquid or the gas flow rate until the pulsing flow regime is reached) and a Super prewetted bed. Pressure drop, liquid holdup and gas–liquid mass transfer are the hydrodynamic parameters studied to quantify the various MHS. It is shown that the shape and extent of the hysteresis cycle are strongly dependant on the prewetting procedure. In terms of flow structure, similar hysteresis trends on the Kan Liquid and Super prewetting modes indicate that these modes are hydrodynamically similar. The additional measurement of the hysteresis behaviour of gas–liquid mass transfer proofs that neither holdup nor pressure drop can be used as an indicator of the distribution uniformity.     

水电站进水塔动水压力研究和探讨

基于理想流体,将进水塔简化成水中悬臂梁体系,推导了其受迫振动时的动力响应方程,给出了进水塔内外表面动水压力的解析表达式。与有限元法、水工抗震规范公式计算结果进行了对比,分析验证了该方法在进水塔结构上的适用性及准确性。结果表明:动水压力表达式与结构振型密切相关。该方法的动水压力曲线趋势与有限元方法相似,均在水面以下某深度处迅速变大及达到最大值后曲线值减小弯回,两者最终在塔体底部收于相近的值;最大值大于有限元法,其最大值处曲线折回明显,幅度较大。弹性模量和进水塔高度对动水压力的曲线形态和数值有重要影响。同时,输入激励荷载的频率对动水压力影响巨大,尤其频率与进水塔某阶频率相近时会导致动水压力的异常增大。该方法对分析进水塔动水压力具有参考价值。     

土坝溃决跌坎水流水动力特性数值模拟

黏性土坝漫顶溃决涉及多学科交叉,过程极其复杂,尽管国内外大量物理模型试验成果表明其溃决多以“跌坎式”溯源冲蚀为主要特征,然而对该冲蚀发展形式下的水流-坝体微观作用机制尚不清晰。水流作为漫顶溃决的冲刷主动力,对坝体溃决发展起着主导性作用,采用RNG k-ε紊流模型和VOF自由液面捕捉技术针对黏性土坝漫顶溃决代表性水流结构——溃决跌坎水流开展了三维数值模拟研究,对跌坎水流的水流结构、流态、水力特性指标等进行了细致分析,揭示了不同工况下坝体跌坎上的剪切应力、流速分布规律,进而从水动力学的角度对坝面进行受力分析,初步推断了黏性土坝漫顶溃决过程中各级跌坎的主要合并方式为“台阶水平面刷深下切”。研究成果为进一步掌握黏性土坝漫顶溃决发展演变机理提供了理论基础。     

高水头船闸一字闸门水动力特性数值模拟

针对某山区高水头船闸30 m淹没水深下一字闸门的水动力特性进行研究,借助FLUENT软件提供的Realizable k-ε紊流模型对门体启闭过程非恒定流场进行动态模拟,通过建立由二维平面混合网格纵向拉伸成的三维棱柱体网格,结合2.5D重构和弹性光顺动网格法,在降低网格数量、提高计算效率的同时,实现一字闸门启闭全过程三维流场模拟。引入VOF法对自由水面迭代求解,得到一字闸门启闭过程门前后水位差及动水阻力矩变化规律,将计算结果与模型试验进行比较,两者吻合较好。模拟计算发现:门底间隙对闸门运行整个阶段动水阻力矩均有影响,动水阻力矩峰值随门底间隙增大而变小。     

Application of an improved control-variate scheme to local neoclassical transport simulations

A new radially local neoclassical transport code is developed based on the radially global two-weight δf$\delta f$ Monte Carlo code, FORTEC-3D (Satake et al., 2008). In the collisional two-weight δf$\delta f$ method, the variance of weight increases in time due to the so-called weight spreading, which leads to an increasing numerical noise in long time simulations. A new improved control-variate scheme was proposed by Kleiber et al. (2011) to reduce the variance. We investigate the effectiveness and validity of the new control-variate scheme for a practical collisional transport problem in a plasma described by the drift kinetic equation. It is demonstrated that the new scheme reduces the variance of weight by approximately 75% in an axisymmetric magnetic field configuration. The burst-like behavior of a transport observable caused by a large numerical noise can be avoided. As a result, the time evolution of a transport observable can be successfully smoothed.     

微孔介质塔板流体力学和传质性能的研究

开发出一种新型微孔介质塔板—泡沫镍塔板 ,并在一个 5 0 0× 5 0 0mm2 有机玻璃方塔内用空气—水系统测定了其流体力学性能指标—塔板压降等 ,用二氧化碳解吸实验测定了塔板效率 ,研究了它们随空塔动能因子、堰高和液流强度变化的规律。实验结果表明 ,此种塔板虽然压降稍大 ,但传质效率很高且没有漏液 ,可用于工业生产中。