Towards the identification of the binding site of benzimidazoles to β-tubulin of Trichinella spiralis: Insights from computational and experimental data

Benzimidazole-2-carbamate derivatives (BzC) are among the most important broad-spectrum anthelmintic drugs for the treatment of nematode infections. BzC selectively bind to the β-tubulin monomer and inhibit microtubule polymerization. However, the crystallographic structure of the nematode tubulin and the mechanism of action are still unknown. Moreover, the relation between the mechanism of action and the binding site of BzC has not yet been explained accurately. By using the amino acid sequence of Trichinella spiralis β-tubulin as a basis and by applying homology modeling techniques, we were able to build a 3D structure of this protein. In order to identify a binding site for BzC, molecular docking and molecular dynamics calculations were carried out with this model. The results were in good agreement with the most common amino acid mutations associated with drug resistance (F167Y, E198A and F200Y) and with the experimental results of competitive inhibition of colchicine binding to tubulin. Besides, Glu198, Thr165, Cys239 and Gln134 were identified as important amino acids in the binding process since they directly interact with BzC in the formation of hydrogen bonds. The results presented in this paper are a step further towards the understanding, at the molecular level, of the mode of action of anthelmintic drugs. These results constitute valuable information for the design or improvement of more potent and selective molecules.     

MASAS—A user-friendly simulation tool for modeling the fate of anthropogenic substances in lakes

MASAS is a computer simulation tool to investigate anthropogenic organic compounds in lakes. Models included are based on a dynamic one-dimensional vertical lake model describing the time-dependent concentration of a compound in the water column and in the sediment. Provision of data is ensured by library files. Interactive specification of transport and transformation processes yields models of different complexity, suitable for the initial assessment of chemicals and for chemodynamic studies. A hypothetical spill of an insecticide (disulfoton) serves as an illustration. Aspects relevant to the development of user-friendly software in the environmental sciences are discussed. User-friendliness is found to depend more on program concepts than on a particular user interface. The management of data sets on lakes and compounds, and the implementation of transport and transformation processes in MASAS exemplify the significance of modularization, program data structures, the use of metaphors, and the distinction between automatic and user-controlled program functions.     

State of the art in damage information modeling for RC bridges – A literature review

In Germany, bridges have an average age of 40 years. A bridge consumes between 0.4% and 2% of its construction cost per year over its entire life cycle. This means that up to 80% of the construction cost are additionally needed for operation, inspection, maintenance, and destruction. Current practices rely either on paper-based inspections or on abstract specialist software. Every application in the inspection and maintenance sector uses its own data model for structures, inspections, defects, and maintenance. Due to this, data and properties have to be transferred manually, otherwise a converter is necessary for every data exchange between two applications. To overcome this issue, an adequate model standard for inspections, damage, and maintenance is necessary. Modern 3D models may serve as a single source of truth, which has been suggested in the Building Information Modeling (BIM) concept. Further, these models offer a clear visualization of the built infrastructure, and improve not only the planning and construction phases, but also the operation phase of construction projects. BIM is established mostly in the Architecture, Engineering, and Construction (AEC) sector to plan and construct new buildings. Currently, BIM does not cover the whole life cycle of a building, especially not inspection and maintenance. Creating damage models needs the building model first, because a defect is dependent on the building component, its properties and material. Hence, a building information model is necessary to obtain meaningful conclusions from damage information. This paper analyzes the requirements, which arise from practice, and the research that has been done in modeling damage and related information for bridges. With a look at damage categories and use cases related to inspection and maintenance, scientific literature is discussed and synthesized. Finally, research gaps and needs are identified and discussed.     

Comparison of templates for homology model of ρ1 GABAC receptors: More insights to the orthosteric binding site’s structure and functionality

Five sets of ρ1 GABA_C homology models were generated based on X-ray crystal structures of the acetylcholine binding protein (AChBP), the ion channel from Caenorhabditis elegans (GLIC), the ion channel from Erwinia chrysanthemi (ELIC), the homomeric GABA_A β₃ ion channel, and the homomeric α-subunit of glutamate-gated homopentameric chloride channel (GluCl). The GluCl based model was found to the represent the structure of ρ1 GABA_C receptors. The GABA pose docked in the selected best model was confirmed by QM-polarized ligand docking and induced fit docking protocol, and used to study molecular interactions in the ρ1 GABA binding site. The potential interactions of identified residues are discussed. This study identified several residues with potential ligand interactions located on loops F and G with their side chain oriented toward the binding site such as Ser215 and Gln83. The partial agonists muscimol and imidazole-4-acetic acid (I4AA) were docked into the binding site of the most reliable ‘GABA bound’ homology model. The potency and efficacy of these partial agonists in activating recombinant ρ1 receptors were correlated with their docking results. The model predicts that muscimol resembles GABA in the docking pose with similar interactions. However, I4AA has a very different docking pose to GABA and was predicted by the model to form π–π stacking with aromatic residues in the orthosteric binding site. A set of TPMPA bound ρ1 homology models based on the GluClα ‘apo state’ template was built in order to study a competitive antagonist in the ρ1 orthosteric binding site. The results demonstrated the ability of our model to explain most experimental findings and predict potential roles of residues within the orthosteric binding site.     

A subject-specific software solution for the modeling and the visualization of muscles deformations

Today, to create and to simulate a virtual anatomical version of a subject is useful in the decision process of surgical treatments. The muscular activity is one of the factors which can contribute to abnormal movements such as in spasticity or static contracture. In this paper, we propose a numerical solution, based on the Finite Element (FE) method, able to estimate muscles deformations during contraction. Organized around a finite element solver and a volumetric environment, this solution is made of all the modeling and simulation processes from the discretization of the studied domain to the visualization of the results. The choices of materials and properties of the FE model are also presented such as the hyperelasticity, the contention model based on inter-meshes neighboring nodes pairing, and the estimation of nodal forces based on the subject-specific muscular forces and action lines.

Mathematical modeling in the geoinformation problem of the dynamics of geomigration under space–time nonlocality

A mathematical model is set up to analyze the dynamics of locally time- and space-nonequilibrium migration–consolidation processes in a porous earth saturated with salt solutions under mass transfer. The corresponding nonlinear boundary-value problem is stated, an algorithm of its approximate solution is presented, and the results of the numerical implementation of the algorithm are given.     

Is it possible to increase hit rates in structure-based virtual screening by pharmacophore filtering? An investigation of the advantages and pitfalls of post-filtering

We have investigated the influence of post-filtering virtual screening results, with pharmacophoric features generated from an X-ray structure, on enrichment rates. This was performed using three docking softwares, zdock+, Surflex and FRED, as virtual screening tools and pharmacophores generated in UNITY from co-crystallized complexes. Sets of known actives along with 9997 pharmaceutically relevant decoy compounds were docked against six chemically diverse protein targets namely CDK2, COX2, ER, fXa, MMP3, and NA. To try to overcome the inherent limitations of the well-known docking problem, we generated multiple poses for each compound. The compounds were first ranked according to their scores alone and enrichment rates were calculated using only the top scoring pose of each compound. Subsequently, all poses for each compound were passed through the different pharmacophores generated from co-crystallized complexes and the enrichment factors were re-calculated based on the top-scoring passing pose of each compound. Post-filtering with a pharmacophore generated from only one X-ray complex was shown to increase enrichment rates in all investigated targets compared to docking alone. This indicates that this is a general method, which works for diverse targets and different docking softwares.     

Social networking site or social surveillance site? Understanding the use of interpersonal electronic surveillance in romantic relationships

Social network sites (SNSs) are commonly used to maintain existing relationships and form connections with new contacts. Recently, concerns of have been expressed over the way these Web-based technologies are used. Estimates suggest that people are increasingly using SNSs for engaging in the surveillance of others. Given the relatively high rates of prevalence, it can be argued that SNSs have been reinvented into a tool for interpersonal surveillance along with their social networking capabilities. This article expands on the concept of interpersonal electronic surveillance and applies it in the specific context of romantic partners’ use of SNSs. The relationships between surveillance over SNSs and demographic, relational, and Internet use and efficacy variables are studied. The findings reveal that interpersonal surveillance over SNSs is influenced by age, the time individuals spend on their partners’ profiles, the integration of SNSs into daily routines, and Internet self-efficacy.     

Discovery of high affinity ligands for β2-adrenergic receptor through pharmacophore-based high-throughput virtual screening and docking

Novel high affinity compounds for human β₂-adrenergic receptor (β₂-AR) were searched among the clean drug-like subset of ZINC database consisting of 9,928,465 molecules that satisfy the Lipinski's rule of five. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive amount of docking and rescoring. The pharmacophore model was composed of key features shared by all five inactive states of β₂-AR in complex with inverse agonists and antagonists. To test the discriminatory power of the pharmacophore model, a small-scale screening was initially performed on a database consisting of 117 compounds of which 53 antagonists were taken as active inhibitors and 64 agonists as inactive inhibitors. Accordingly, 7.3% of the ZINC database subset (729,413 compounds) satisfied the pharmacophore requirements, along with 44 antagonists and 17 agonists. Afterwards, all these hit compounds were docked to the inactive apo form of the receptor using various docking and scoring protocols. Following each docking experiment, the best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity. After final evaluations based on the human intestinal absorption (HIA) and the blood brain barrier (BBB) penetration properties, 62 hit compounds have been clustered based on their structural similarity and as a result four scaffolds were revealed. Two of these scaffolds were also observed in three high affinity compounds with experimentally known K_i values. Moreover, novel chemical compounds with distinct structures have been determined as potential β₂-AR drug candidates.     

In silico analysis of the binding of agonists and blockers to the β2-adrenergic receptor

Activation of G protein-coupled receptors (GPCRs) is a complex phenomenon. Here, we applied Induced Fit Docking (IFD) in tandem with linear discriminant analysis (LDA) to generate hypotheses on the conformational changes induced to the β(2)-adrenergic receptor by agonist binding, preliminary to the sequence of events that characterize activation of the receptor. This analysis, corroborated by a follow-up molecular dynamics study, suggested that agonists induce subtle movements to the fifth transmembrane domain (TM5) of the receptor. Furthermore, molecular dynamics also highlighted a correlation between movements of TM5 and the second extracellular loop (EL2), suggesting that freedom of motion of EL2 is required for the agonist-induced TM5 displacement. Importantly, we also showed that the IFD/LDA procedure can be used as a computational means to distinguish agonists from blockers on the basis of the differential conformational changes induced to the receptor. In particular, the two most predictive models obtained are based on the RMSD induced to Ser207 and on the counterclockwise rotation induced to TM5.     

Erratum to: New efficient method for dynamic modeling and simulation of flexible multibody systems moving in plane

Efficient, precise dynamic analysis for general flexible multibody systems has become a research focus in the field of flexible multibody dynamics. In this paper, the finite element method and component mode synthesis are introduced to describe the deformations of the flexible components, and the dynamic equations of flexible bodies moving in plane are deduced. By combining the discrete time transfer matrix method of multibody system with these dynamic equations of flexible component, the transfer equations and transfer matrices of flexible bodies moving in plane are developed. Finally, a high-efficient dynamic modeling method and its algorithm are presented for high-speed computation of general flexible multibody dynamics. Compared with the ordinary dynamics methods, the proposed method combines the strengths of the transfer matrix method and finite element method. It does not need the global dynamic equations of system and has the low order of system matrix and high computational efficiency. This method can be applied to solve the dynamics problems of flexible multibody systems containing irregularly shaped flexible components. It has advantages for dynamic design of complex flexible multibody systems. Formulations as well as a numerical example of a multi-rigid-flexible-body system containing irregularly shaped flexible components are given to validate the method.     

Determination of the protonation state for the catalytic dyad in β-secretase when bound to hydroxyethylamine transition state analogue inhibitors: A molecular dynamics simulation study

BACE1 is an aspartyl protease of pharmacological interest for its direct participation in Alzheimer’s disease (AD) through β-amyloid peptide production. Two aspartic acid residues are present in the BACE1 catalytic region which can adopt multiple protonation states depending on the chemical nature of its inhibitors, i.e., monoprotonated, diprotonated and di-deprotonated states. In the present study a series of protein-ligand molecular dynamics (MD) simulations was carried out to identify the most feasible protonation state adopted by the catalytic dyad in the presence of hydroxyethylamine transition state analogue inhibitors. The MD trajectories revealed that the di-deprotonated state is most prefered in the presence of hydroxyethilamine (HEA) family inhibitors. This appears as a result after evaluating, for all 9 protonation state configurations during the simulation time, the deviations of a set of distances and dihedral angles measured on the ligand, protein and protein-ligand complex with reference to an X-ray experimental BACE1/HEA crystallographic structure. These results will help to clarify the phenomena related to the HEAs inhibitory pathway, and improve HEAs databases’ virtual screening and ligand design processes targeting β-secretase protein.     

Assessment of offload-based programming environments for hybrid CPU–MIC platforms in numerical modeling of solidification

Heterogeneous (or hybrid) computing platforms with Intel Xeon Phi accelerators offer potential advantages of energy efficient, massively parallel computing, while supporting parallel programming models familiar for users of multicore CPUs. However, realizing this potential for real-world applications still remains a challenging issue. The main goal of this paper is the suitability assessment of offload-based programming environments for porting a real-life scientific application to hybrid platforms with Intel KNC and KNL accelerators, assuming no significant modifications of the application code. The main criterion of this assessment is the application performance. The evaluated environments include: 1) Intel Offload coupled with OpenMP, 2) OpenMP 4.0 and 3) OpenMP 4.5 Accelerator Models, and 4) hStreams Library with OpenMP. A real-life application dedicated to the numerical modeling of alloy solidification is used as a testbed in the assessment. An experimental evaluation of the four versions of the application code for a platform with KNC coprocessors shows that excluding OpenMP 4.0, the rest of them are able to adapt to expansion of available resources, however, with different efficiency. While the shortest execution time is achieved for Intel Offload, the high-level abstractions of hStreams contribute considerably to making porting and tuning the application easier, with low performance overheads in comparison to the low-level Intel Offload extension. Benchmarking the application performance and scalability on a platform with multiple KNL processors, using the Offload over Fabric technology with Intel Offload and OpenMP 4.5, concludes the assessment.     

Neuro–fuzzy modeling tools for estimation of torque in Savonius rotor wind turbine

In the present paper, the ability and accuracy of an adaptive neuro–fuzzy inference system (ANFIS) has been investigated for dynamic modeling of wind turbine Savonius rotor. The main objective of this research is to predict torque performance as a function of the angular position of turbine. In order to better understanding the present technique, the dynamic performance modeling of a Savonius rotor is an important consideration for the wind turbine design procedure. It could be difficult to derive the exact mathematical derivation for the input–output relationships because of the complexity of the design algorithm. In order to show the best fitted algorithm, an extensive comparison test was applied on the ANFIS (adaptive neuro–fuzzy inference system), FIS (fuzzy inference system), and RBF (radial basis function). Resulting from the extensive comparison test, the ANFIS procedure yields very accurate results in comparison with two alternate procedures. The results show that there is an excellent agreement between the testing data (not used in training) and estimated data, with average errors very low. Also FIS with threshold 0.05 and the trained ANFIS are able to accurately capture the non-linear dynamics of torque even for a new condition that has not been used in the training process (testing data). For the sake of comparison, the results of the proposed ANFIS model is compared with those of the RBF model, as well. For implementation of the present technique, the Matlab codes and related instructions are efficiently used, respectively.     

Use of third generation data for the elements to model the thermodynamics of binary alloy systems: Part 1 – The critical assessment of data for the Al-Zn system

Over the last four years there has been a renewed interest in the development of new critically assessed data using physically based models. Nearly all work so far has been concerned with the critical assessment of data for the elements. This has involved the selection of Einstein or Debye temperatures for the stable crystalline phases and the liquid phase and associated parameters. However, until now, these data have not been extended in a comprehensive way to model the thermodynamic properties of binary, ternary and multicomponent systems. In this paper the way in which the parameters underlying these physical models vary with composition is explored. This includes a method to define the Einstein temperature for metastable phases of the elements and its relation to the so-called lattice stabilities used in the past, and the variation of the Einstein temperature with composition to account for the composition dependence of the excess entropy. This approach is demonstrated for the Al-Zn system which shows extensive regions of solid solution and complete miscibility in the liquid phase. Here Einstein temperatures are derived for Al in the HCP_ZN phase and Zn in the FCC_A1 phase together with parameters describing the variation of the Einstein temperature with composition for the HCP_ZN, FCC_A1 and liquid phases.