Molecular Docking Studies and Biological Evaluation of Berberine–Benzothiazole Derivatives as an Anti-Influenza Agent via Blocking of Neuraminidase

In this study, we have introduced newly synthesized substituted benzothiazole based berberine derivatives that have been analyzed for their in vitro and in silico biological properties. The activity towards various kinds of influenza virus strains by employing the cytopathic effect (CPE) and sulforhodamine B (SRB) assay. Several berberine–benzothiazole derivatives (BBDs), such as BBD1, BBD3, BBD4, BBD5, BBD7, and BBD11, demonstrated interesting anti-influenza virus activity on influenza A viruses (A/PR/8/34, A/Vic/3/75) and influenza B viral (B/Lee/40, and B/Maryland/1/59) strain, respectively. Furthermore, by testing neuraminidase activity (NA) with the neuraminidase assay kit, it was identified that BBD7 has potent neuraminidase activity. The molecular docking analysis further suggests that the BBD1–BBD14 compounds’ antiviral activity may be because of interaction with residues of NA, and the same as in oseltamivir.     

Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca²⁺-dependent ion channels and/or Ca²⁺-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.     

Novel Cell Permeable Polymers of N-Substituted L-2,3-Diaminopropionic Acid (DAPEGs) and Cellular Consequences of Their Interactions with Nucleic Acids

The present study aimed to synthesize novel polycationic polymers composed of N-substituted L-2,3-diaminopropionic acid residues (DAPEGs) and investigate their cell permeability, cytotoxicity, and DNA-binding ability. The most efficient cell membrane-penetrating compounds (O2Oc-Dap(GO2)_n-O2Oc-NH₂, where n = 4, 6, and 8) showed dsDNA binding with a binding constant in the micromolar range (0.3, 3.4, and 0.19 µM, respectively) and were not cytotoxic to HB2 and MDA-MB-231 cells. Selected compounds used in the transfection of a GFP plasmid showed high transfection efficacy and minimal cytotoxicity. Their interaction with plasmid DNA and the increasing length of the main chain of tested compounds strongly influenced the organization and shape of the flower-like nanostructures formed, which were unique for 5/6-FAM-O2Oc-[Dap(GO2)]₈-O2Oc-NH₂ and typical for large proteins.     

Adaptive simulated annealing particle swarm optimization algorithm

Particle swarm optimization is widely used in various fields because of the few parameters to be set and the simple calculation structure.In order to improve the optimization speed and accuracy of the PSO,and to avoid falling into the local optimal solution,an adaptive simulated annealing PSO is proposed,which uses the hyperbolic tangent function to control the inertia weight factor for nonlinear adaptive changes,uses linear change strategies to control 2 learning factors,introduces the simulation annealing operation,set a temperature according to the initial state of the population,guide the population to accept the difference solution with a certain probability according to the Metropolis criterion,and ensure the ability to jump out of the local optimal solution.To verify the effect of the algorithm proposed in this paper,7 typical test functions and 5 algorithms proposed in the literature are selected for comparison and testing.According to the average value,standard deviation and number of iterations of the optimization results,the algorithm proposed in this paper has greatly improved the iteration accuracy,convergence speed and stability so as to overcome the shortcomings of particle swarm optimization.     

分子筛辅助人参须根粉快速制备人参皂苷Rg5的工艺研究

利用多功能改进型索氏提取器为提取工具,以人参须根粉为原料,盐酸为催化剂,分子筛辅助下高效制备了稀有人参皂苷Rg5,并通过单因素实验优化了工艺条件。实验结果表明：当以30 mL的甲醇为溶剂、加入0.3 g 4 A分子筛、于65 ℃提取4 h时,人参总皂苷的提取率达到10.2%,稀有人参皂苷Rg5的得率达到3.20%,与传统索氏提取器相比可以显著提高人参皂苷Rg5的制备效率。分子筛辅助下利用多功能改进型索氏提取器从人参须根粉提取制备稀有人参皂苷Rg5,不仅得率较高,而且操作简单快捷,是一种快速制备人参皂苷Rg5的工艺方法。     

一种新的动态权重更新相关反馈方法*

提出了正负相关图像所占比例与特征值的标准方差相结合来调整对应权值的方法.为了避免相关反馈的权值调整陷入局部最优状态,引入一个干扰因子,使权值跳出局部最优区域.结果表明了该方法的优越性.     

加权平均量的自收敛性与权的确定

在多因素综合评价决策中,合理确定各因素权重系数是评价决策的关键。文章引入了加权平均量的自收敛性来描绘被评价分数的随机变量的稳定性,以概率论理论为基础,得到了一般情况下权重系数确定的优化模型和协方差矩阵为正定矩阵的一系列的确定权的方法,建立了一套较完整的确定权重系数的理论。     

改进的永磁同步电机双矢量模型预测转矩控制

针对永磁同步电机（PMSM）传统模型预测转矩控制（MPTC）权重系数设置复杂、转矩和磁通脉动大的问题,提出了一种改进的PMSM双矢量MPTC方法。该方法扩展虚拟矢量以增加候选电压矢量,结合电压矢量作用于转矩和磁链的原则,减少选择候选矢量的计算量。同时,针对转矩无差拍和磁通无差拍,运用候选矢量的转矩占空比和磁通占空比构造了优化规则代替传统预测转矩控制中的代价函数,避免权重系数的整定问题。仿真结果表明,所提改进方法不仅提高稳态性能,而且能保持MPTC动态响应迅速的特点。     

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.     

Structural Investigation and Molecular Modeling Studies of Strobilurin-Based Fungicides Active against the Rice Blast Pathogen Pyricularia oryzae

The increasing emergence of fungicide-resistant pathogens requires urgent solutions for crop disease management. Here, we describe a structural investigation of new fungicides obtained by combining strobilurin and succinate dehydrogenase inhibitor pharmacophores. We identified compounds endowed with very good activity against wild-type Pyricularia oryzae, combined in some cases with promising activity against strobilurin-resistant strains. The first three-dimensional model of P. oryzae cytochrome bc1 complex containing azoxystrobin as a ligand was developed. The model was validated with a set of commercially available strobilurins, and it well explains both the resistance mechanism to strobilurins mediated by the mutation G143A and the activity of metyltetraprole against strobilurin-resistant strains. The obtained results shed light on the key recognition determinants of strobilurin-like derivatives in the cytochrome bc1 active site and will guide the further rational design of new fungicides able to overcome resistance caused by G143A mutation in the rice blast pathogen.