Strategies for the determination of pharmacophoric 3D database queries

Strategies are described for constructing pharmacophoric 3D database queries, based on aseries of active and inactive analogs. The results are highly selective database queries, whichare consistent with the generally accepted pharmacophore for a number of systems. Thefoundation of these strategies is the method of Mayer, Naylor, Motoc and Marshall [J.Comput.-Aided Mol. Design, 1 (1987) 3] for inferring a unique binding geometry forangiotensin-converting enzyme (ACE) inhibitors. The strategies described here generalize theirapproach to cases where the chemical features responsible for binding are not a prioriapparent, and to cases where the binding geometry deduced by that method is not unique. Thekey new insight, the selectivity principle, is to rank the multiple solutions produced by themethod of Mayer et al. by their selectivity, a value that is related to the proportion of adatabase that is returned as a database hit list. Retrospective analyses are described for D2-antagonists, ACE inhibitors, fibrinogen antagonists, and 2-antagonists.     

基于Unity 3D的气相色谱仪虚拟仿真实验系统的构建

虚拟仿真技术被广泛认为是一项重大技术进步,可以提供一种新颖的教学方式,能促进化学学习,打破传统教育方法的限制。三维交互式的气相色谱仪虚拟仿真实验系统使用当前主流的Unity 3D软件作为系统的主要开发工具。构建的系统主要包含仪器的动态原理展示、三维结构展示及仿真实验3部分。系统中的模型全部采用三维设计,场景逼真,能够全方位地向使用者展现真实仪器的外形及内部结构,令使用者如同置身于真实实验室中,获得身临其境的操作体验,从而更容易学习和掌握仪器组成、工作原理及相关的实验技能。系统不仅满足了仪器培训和化学实验教学的基本需求,而且对虚拟仿真技术在化学中的应用起了示范效应和推广作用。     

Facility-based inspection training in a virtual 3D laboratory

In order to train postgraduate students in the evaluation of a quality system in the pharmaceutical industry, it would be desirable to have installations constructed in accordance with the quality standards. This is very costly and unusual in universities. Virtual 3D worlds allow simulating immersive professional contexts for training. The first aim of this project is to design and construct a virtual analytical laboratory adapted to good laboratory practices (GLP) in the Second Life? (SL) virtual world. The second aim is to set up a practice based on the inspection of the virtual laboratory installations. Finally, the students’ acquisition of knowledge and satisfaction were assessed. The laboratory is available online on the Usalpharma Island of SL. The installations, equipment and tools were created using SL’s building tools. During two academic years, a total of 30 students made an inspection of the laboratory to identify and classify nonconformities of a GLP quality system (supplementary video). They report the results in an assessment report. The following evaluation of the practice shows that the scores concerning the assessment of skills (7.1 ± 0.5 out of 10) and knowledge acquired (7.8 ± 0.3 out of 10) met the expectations of the authors. In an anonymous questionnaire, 81 % of the students assessed the experiment as satisfactory. The virtual laboratory allows, at very low cost, training postgraduate students in facilities not available at university. Tools like this could be implemented not only at universities, but in professional field in order to assess competencies or support the essential lifelong learning of the laboratory staff.     

Performance evaluation of 2D fingerprint and 3D shape similarity methods in virtual screening

Virtual screening (VS) can be accomplished in either ligand- or structure-based methods. In recent times, an increasing number of 2D fingerprint and 3D shape similarity methods have been used in ligand-based VS. To evaluate the performance of these ligand-based methods, retrospective VS was performed on a tailored directory of useful decoys (DUD). The VS performances of 14 2D fingerprints and four 3D shape similarity methods were compared. The results revealed that 2D fingerprints ECFP_2 and FCFP_4 yielded better performance than the 3D Phase Shape methods. These ligand-based methods were also compared with structure-based methods, such as Glide docking and Prime molecular mechanics generalized Born surface area rescoring, which demonstrated that both 2D fingerprint and 3D shape similarity methods could yield higher enrichment during early retrieval of active compounds. The results demonstrated the superiority of ligand-based methods over the docking-based screening in terms of both speed and hit enrichment. Therefore, considering ligand-based methods first in any VS workflow would be a wise option.     

Toward high throughput 3D virtual screening using spherical harmonic surface representations

Searching chemical databases for possible drug leads is often one of the main activities conducted during the early stages of a drug development project. This article shows that spherical harmonic molecular shape representations provide a powerful way to search and cluster small-molecule databases rapidly and accurately. Our clustering results show that chemically meaningful clusters may be obtained using only low order spherical harmonic expansions. Our database search results show that using low order spherical harmonic shape-based correlation techniques could provide a practical and efficient way to search very large 3D molecular databases, hence leading to a useful new approach for high throughput 3D virtual screening. The approach described is currently being extended to allow the rapid search and comparison of arbitrary combinations of molecular surface properties.     

Aligned carbon nanostructures based 3D electrodes for energy storage

Electrochemical energy storage systems with high specific energy and power as well as long cyclic stability attract increasing attention in new energy technologies. The principles for rational design of electrodes are discussed to reduce the activation, concentration, and resistance overpotentials and improve the active material efficiency in order to simultaneously achieve high specific energy and power. Three dimensional(3D)nanocomposites are currently considered as promising electrode materials due to their large surface area,reduced electronic and ionic diffusion distances, and synergistic effects. This paper reviews the most recent progress on the synthesis and application of 3D thin film nanoelectrode arrays based on aligned carbon nanotubes(ACNTs) directly grown on metal foils for energy storages and special attentions are paid on our own representative works. These novel 3D nanoelectrode arrays on metal foil exhibit improved electrochemical performances in terms of specific energy, specific power and cyclic stability due to their unique structures.In this active materials coated ACNTs over conductive substrate structures, each component is tailored to address a different demand. The electrochemical active material is used to store energy, while the ACNTs are employed to provide a large surface area to support the active material and nanocable arrays to facilitate the electron transport. The thin film of active materials can not only reduce ion transport resistance by shortening the diffusion length but also make the film elastic enough to tolerate significant volume changes during charge and discharge cycles. The conductive substrate is used as the current collector and the direct contact of the ACNT arrays with the substrate reduces significantly the contact resistance. The principles obtained from ACNT based electrodes are extended to aligned graphene based electrodes. Similar improvements have been achieved which confirms the reliability of the principles obtained. In addition, we also discuss and view the ongoing trends in development of aligned carbon nanostructures based electrodes for energy storage.     

Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge

Induced fit or protein flexibility can make a given structure less useful for docking and/or scoring. The 2015 Drug Design Data Resource (D3R) Grand Challenge provided a unique opportunity to prospectively test optimal strategies for virtual screening in these type of targets: heat shock protein 90 (HSP90), a protein with multiple ligand-induced binding modes; and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a kinase with a large flexible pocket. Using previously known co-crystal structures, we tested predictions from methods that keep the receptor structure fixed and used (a) multiple receptor/ligand co-crystals as binding templates for minimization or docking (“close”), (b) methods that align or dock to a single receptor (“cross”), and (c) a hybrid approach that chose from multiple bound ligands as initial templates for minimization to a single receptor (“min-cross”). Pose prediction using our “close” models resulted in average ligand RMSDs of 0.32 and 1.6 Å for HSP90 and MAP4K4, respectively, the most accurate models of the community-wide challenge. On the other hand, affinity ranking using our “cross” methods performed well overall despite the fact that a fixed receptor cannot model ligand-induced structural changes,. In addition, “close” methods that leverage the co-crystals of the different binding modes of HSP90 also predicted the best affinity ranking. Our studies suggest that analysis of changes on the receptor structure upon ligand binding can help select an optimal virtual screening strategy.     

QM/MM based 3D QSAR models for potent B-Raf inhibitors

Three dimensional (3D) quantitative structure-activity relationship studies of 37 B-Raf inhibitors, pyrazole-based derivatives, were performed. Based on the co-crystallized compound (PDB ID: 3D4Q), several alignment methods were utilized to derive reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. Receptor-guided alignment with quantum mechanics/molecular mechanics (QM/MM) minimization led to the best CoMFA model (q ² = 0.624, r ² = 0.959). With the same alignment, a statistically reliable CoMSIA model with steric, H-bond acceptor, and hydrophobic fields was also derived (q ² = 0.590, r ² = 0.922). Both models were validated with an external test set, which gave satisfactory predictive r ² values of 0.926 and 0.878, respectively. Contour maps from CoMFA and CoMSIA models revealed important structural features responsible for increasing biological activity within the active site and explained the correlation between biological activity and receptor-ligand interactions. New fragments were identified as building blocks which can replace R1-3 groups through combinatorial screening methods. By combining these fragments a compound with a high bioactivity level prediction was found. These results can offer useful information for the design of new B-Raf inhibitors.     

Lithium-sulphur batteries based on biological 3D structures

Journal of Solid State Electrochemistry - Lithium-sulphur accumulators are, thanks to their high theoretical energy density and good availability of sulphur, one of the most promising concepts of...     

SHAFTS: a hybrid approach for 3D molecular similarity calculation. 1. Method and assessment of virtual screening

We developed a novel approach called SHAFTS (SHApe-FeaTure Similarity) for 3D molecular similarity calculation and ligand-based virtual screening. SHAFTS adopts a hybrid similarity metric combined with molecular shape and colored (labeled) chemistry groups annotated by pharmacophore features for 3D similarity calculation and ranking, which is designed to integrate the strength of pharmacophore matching and volumetric overlay approaches. A feature triplet hashing method is used for fast molecular alignment poses enumeration, and the optimal superposition between the target and the query molecules can be prioritized by calculating corresponding "hybrid similarities". SHAFTS is suitable for large-scale virtual screening with single or multiple bioactive compounds as the query "templates" regardless of whether corresponding experimentally determined conformations are available. Two public test sets (DUD and Jain's sets) including active and decoy molecules from a panel of useful drug targets were adopted to evaluate the virtual screening performance. SHAFTS outperformed several other widely used virtual screening methods in terms of enrichment of known active compounds as well as novel chemotypes, thereby indicating its robustness in hit compounds identification and potential of scaffold hopping in virtual screening.     

3D metal-organic frameworks based on elongated tetracarboxylate building blocks for hydrogen storage

Two 3D metal-organic frameworks (MOFs) with a new biphenol-derived tetracarboxylate linker and Cu(II) and Zn(II) metal-connecting points were synthesized and characterized by single-crystal X-ray crystallographic studies. The two isostructural MOFs exhibit distorted PtS network topology and show markedly different framework stability. The porosity and hydrogen uptake of the frameworks were determined by gas adsorption experiments.     

Structure-based rational quest for potential novel inhibitors of human HMG-CoA reductase by combining CoMFA 3D QSAR modeling and virtual screening

3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) catalyzes the formation of mevalonate. In many classes of organisms, this is the committed step leading to the synthesis of essential compounds, such as cholesterol. However, a high level of cholesterol is an important risk factor for coronary heart disease, for which an effective clinical treatment is to block HMGR using inhibitors like statins. Recently the structures of catalytic portion of human HMGR complexed with six different statins have been determined by a delicate crystallography study (Istvan and Deisenhofer Science 2001, 292, 1160-1164), which established a solid basis of structure and mechanism for the rational design, optimization, and development of even better HMGR inhibitors. In this study, three-dimensional quantitative structure-activity relationship (3D QSAR) with comparative molecular field analysis (CoMFA) was performed on a training set of up to 35 statins and statin-like compounds. Predictive models were established by using two different ways: (1) Models-fit, obtained by SYBYL conventional fit-atom molecular alignment rule, has cross-validated coefficients (q2) up to 0.652 and regression coefficients (r2) up to 0.977. (2) Models-dock, obtained by FlexE by docking compounds into the HMGR active site, has cross-validated coefficients (q2) up to 0.731 and regression coefficients (r2) up to 0.947. These models were further validated by an external testing set of 12 statins and statin-like compounds. Integrated with CoMFA 3D QSAR predictive models, molecular surface property (electrostatic and steric) mapping and structure-based (both ligand and receptor) virtual screening have been employed to explore potential novel hits for the HMGR inhibitors. A representative set of eight new compounds of non-statin-like structures but with high pIC(50) values were sorted out in the present study.     

From 2D Graphene Nanosheets to 3D Graphene‐based Macrostructures

The combination of exceptional functionalities offered by 3D graphene‐based macrostructures (GBMs) has attracted tremendous interest. 2D graphene nanosheets have a high chemical stability, high surface area and customizable porosity, which was extensively researched for a variety of applications including CO₂ adsorption, water treatment, batteries, sensors, catalysis, etc. Recently, 3D GBMs have been successfully achieved through few approaches, including direct and non‐direct self‐assembly methods. In this review, the possible routes used to prepare both 2D graphene and interconnected 3D GBMs are described and analyzed regarding the involved chemistry of each 2D/3D graphene system. Improvement of the accessible surface of 3D GBMs where the interface exchanges are occurring is of great importance. A better control of the chemical mechanisms involved in the self‐assembly mechanism itself at the nanometer scale is certainly the key for a future research breakthrough regarding 3D GBMs.     

Genetic screens and selections for small molecules based on a synthetic riboswitch that activates protein translation

Genetic selection provides the most powerful method to assay large libraries of biomolecules for function. However, harnessing the power of genetic selection for the detection of specific, nonendogenous small-molecule targets in vivo remains a significant challenge. The ability to genetically select for small molecules would provide a reaction-independent mechanism to clone biosynthesis genes from large DNA libraries and greatly facilitate the exploration of large libraries of mutant enzymes for improved synthetic capabilities including altered substrate specificities and enhanced regio- or stereoselectivities. While remarkable progress has been made in developing genetic methods to detect small molecules in vivo, many of these methods rely on engineering small-molecule-protein interactions which remains a difficult problem, and the potential for some of these systems to assay large libraries is limited by the low transformation efficiency and long doubling time of yeast relative to bacteria. Herein, we demonstrate that synthetic riboswitches that activate protein translation in response to a specific small molecule can be used to perform sensitive genetic screens and selections for the presence of small molecules in Escherichia coli. We further demonstrate that the exquisite molecular discrimination properties of aptamers selected in vitro translate directly into an in vivo genetic selection system. Finally, we demonstrate that a cell harboring a synthetic riboswitch with a particular ligand specificity can be selectively amplified from a million-fold larger pool of cells containing mutant riboswitches that respond to a closely related ligand, suggesting that it is possible to use genetic selection in E. coli to discover synthetic riboswitches with new ligand specificities from libraries of mutant riboswitches.     

Metal-free current collectors based on graphene materials for supecapacitors produced by 3D printing

Supercapacitor (SC) current collectors with electrodes made of graphite oxide reduced during microwave exfoliation are produced from a commercial filament with a graphene component via layer-by-layer fusing with a 3D printer. The separator is made of a graphene oxide film. The current collectors are investigated by means of IR spectroscopy. Electrochemical tests are performed for the assembled SC that include tests of its cyclic stability up to 1000 cycles.

     

The performance of density functional and wavefunction‐based methods for 2D and 3D structures of Au10

The transition from 2D to 3D structures in small gold clusters occurs around 10 atoms. Density functional theory predicts a planar structure for in contrast to recent second‐order Møller–Plesset perturbation theory calculations, which predict a 3D arrangement. The validity of the use of single‐reference second‐order Møller–Plesset theory for near metallic systems remains, however, questionable. On the other hand, it is less than clear how well density functional approximations perform for such clusters. We, therefore, decided to carry out quantum chemical calculations for using a variety of different density functionals as well as wavefunction‐based methods including coupled cluster theory to compare the different energetically low lying 2D and 3D cluster isomers. The results are perhaps not encouraging showing that most computational methods do not predict correctly the energetic sequence of isomers compared to coupled cluster theory. As perturbative triple corrections in the coupled cluster treatment change the order in cluster stability, the onset of 2D to 3D transition in these gold clusters remains elusive. As expected, second‐order Møller–Plesset theory is not suitable for correctly describing such systems.     

Aluminum nitride based 3D,piezoelectric, tactile sensor

A 3D tactile sensing element concept based on tridimensional piezoelectric aluminum nitride (AlN) membranes is presented. Detection modes for normal and shear forces are investigated by FEM simulations. Based on these results a design of a functionalized sensing system is performed. The simulation focuses on the mechanical response of pyramidal structures on force transmission across the whole membrane surface. Therefore, an embedded device configuration is defined. The overall aim of these investigations is to find an optimized sensor electrode configuration and to verify the ability to detect normal and shear forces with one element. Additionally, first high aspect ratio pyramidal AlN membrane structures have been successfully fabricated.