Simple Structural Changes Research Articles

Conformational Control of Tetrahydropyran‐Based Hybrid Dipeptide Catalysts Improves Activity and Stereoselectivity

AbstractHerein, we introduce and demonstrate how carbohydrates can be used as conformational control units of organocatalysts to tune their catalytic properties. New hybrid dipeptide‐like organocatalysts based on ζ‐sugar aminoacids and proline were prepared and tested for the asymmetric Michael addition of aldehydes to β‐nitrostyrenes. Taking full advantage of the modular nature of the carbohydrate motif, both reactivity and stereoselectivity were significantly improved. By simple structural changes, such as the elimination of the methoxy group in the C4 position of the tetrahydropyran ring, we obtained two complementary catalysts that allow access to both enantiomers of the γ‐nitroaldehydes with excellent yields, diastereoselectivity, and enantiomeric excesses between 97 and 99%, using a catalytic load even below 1 mol%.magnified image

Gambling, motor cautiousness, and choice impulsivity: An experimental study

BackgroundImpulsivity is currently more commonly regarded as multifaceted, comprising both motor and cognitive subdomains. However, it is less clear how distinct these subdomains are, and the extent to which they interact and draw upon the same psychological resources.MethodsThe present experiment comprised 70 regular (non-problem) gamblers, and investigated the potential to induce impulsivity transfer effects within an electronic gambling context. Original and existing harm-minimization approaches were tested for their efficacy in inducing motor cautiousness during an electronic slot machine simulation. Participants were exposed to a forced discriminatory motor choice procedure, or pop-up responsible gambling messages that either contained emotive or non-emotive responsible gambling content. The subsequent impact these interventions had on delay discounting and reflection impulsivity was also measured using the 27-item Monetary Choice Questionnaire and Information Sampling Task, respectively.ResultsFindings demonstrated that only original harm-minimization approaches, which force the gambler to engage in discriminatory motor choice procedures during gambling, were successful in inducing motor cautiousness. However, both the discriminatory choice procedure and emotive message harm-minimization approaches were successful in facilitating cognitive choice, even though the emotive message intervention was unsuccessful in facilitating motor response inhibition, suggesting both an indirect motor cautiousness route, and a more direct route to improved cognitive choice during gambling.ConclusionThis study demonstrated that decision-making during gambling can be improved by making simple structural changes to slot machine platforms, by encouraging active engagement in motor processes, which result in a transfer of cautiousness to wider cognitive domains.

Learning from the Ones that Got Away: Detecting New Forms of Phishing Attacks

Phishing attacks continue to pose a major threat for computer system defenders, often forming the first step in a multi-stage attack. There have been great strides made in phishing detection; however, some phishing emails appear to pass through filters by making simple structural and semantic changes to the messages. We tackle this problem through the use of a machine learning classifier operating on a large corpus of phishing and legitimate emails. We design SAFe-PC (Semi-Automated Feature generation for Phish Classification), a system to extract features, elevating some to higher level features, that are meant to defeat common phishing email detection strategies. To evaluate SAFe-PC , we collect a large corpus of phishing emails from the central IT organization at a tier-1 university. The execution of SAFe-PC on the dataset exposes hitherto unknown insights on phishing campaigns directed at university users. SAFe-PC detects more than 70 percent of the emails that had eluded our production deployment of Sophos, a state-of-the-art email filtering tool. It also outperforms SpamAssassin, a commonly used email filtering tool. We also developed an online version of SAFe-PC , that can be incrementally retrained with new samples. Its detection performance improves with time as new samples are collected, while the time to retrain the classifier stays constant.

Improved performance of non-fullerene polymer solar cells by simple structural change of asymmetric acceptor based on indenothiophene

In this study, we have synthesized a new asymmetric n-type semiconducting molecule (Me-ITBD) by combining 4,4-bis(4-hexylphenyl)-7-methyl-6-(thiophen-2-yl)-4H-indeno[1,2-b]thiophene with 2-(benzo[c][1,2,5]-thiadiazol-4-yl methylene)-malononitrile and applied it to polymer solar cells.Compared to the PhITBD acceptor without methyl substituent in the 7-position of the core, Me-ITBD showed a larger torsional angle between thiophene and indenothiophene. Non-fullerene polymer solar cells (PSCs) with the methyl-substituted asymmetric acceptor Me-ITBD displayed an enhanced power conversion efficiency (PCE) of 5.75%, compared to the PSC (PCE = 1.79%) based on a PhITBD acceptor. The higher PCE value of the Me-ITBD-based PSC was ascribed to its improved device parameters, i.e. the Jsc and FF, induced by a favorable fine morphology in the active layer. By simply introducing a methyl substituent in the indenothiophene unit of the PhITBD acceptor, the PSC performance was enhanced.

Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling

Meso-Diaminopimelic acid (meso-2,6-diamino-heptanedioic acid, DAP) is an important component of the cell wall of many bacteria. Meso-diaminopimelate dehydrogenase (m-Ddh) is a critical enzyme in the process of converting tetrahydrodipicolinate to DAP. Here, we are proposing that DAP analogs targeting m-Ddh may be considered as potential antibiotics. Four DAP analogs without significant structural change from DAP have been obtained and their inhibitory potencies against m-Ddh from the P. gingivalis strain W83 show significant differences from that of DAP. However, their inhibitory mechanisms as for how simple structural change influences the inhibitory potency remain unknown. Therefore, we employed molecular modeling methods to obtain insight into the inhibitory mechanisms of DAP and analogs with m-Ddh. The predicted binding mode of DAP was highly consistent with the experimental structural data and disclosed the important roles played by the binding pocket residues. According to our predictions, the isoxazoline ring of compounds 1 and 2 and the double bonds in compounds 3 and 4 had distinct influences on these compounds' binding to m-Ddh. This enriched understanding of the inhibitory mechanisms of DAP and these four analogs to m-Ddh has provided new and relevant information for future rational development of potent inhibitors targeting m-Ddh.

A comprehensive computational mutation structurefunction approach for determining potential drug target sites in poliovirus 2A protease

Purpose : To investigate a computational approach for analysing the structure-function relationship of poliovirus 2A protease using various bioinformatics tools. Methods : The three-dimensional structure of 2Apro was modelled and analyzed using the crystal structure of coxsakievirus B4 as a template to understand the function of this protein. Structural validation programs, VADAR and QMEAN, were used to verify the 2Apro model. Analysis of protein stability changes in poliovirus 2A protease-mutated sequences using various servers was also performed. Furthermore, mutation pattern, intrinsic disorder regions (IDRs), hydrophobic regions, drug binding sites (DBS) and subcellular localization were identified. Results : Hydrophobicity results confirmed the suitability and reliability of 2A protease as a potential drug target. Less IDRs were observed in the protein. Moreover, the results showed the presence of various important drug binding targets among conserved regions of the protease. The predicted drug binding sites indicate their suitability for the inhibition and development of anti-viral drugs against poliovirus 2A protease. Conclusion : The current study resulted in the detection of important ligand interactions with respect to the binding site of the targeted protein. Thus, these compounds may be potent drug candidates and their potency may be increased against poliovirus 2A protease with relatively simple structural changes. Keywords : 2A Protease, Computational analysis, Drug binding sites, Intrinsic disorder regions, Hydrophobicity

Nonpher: computational method for design of hard-to-synthesize structures

In cheminformatics, machine learning methods are typically used to classify chemical compounds into distinctive classes such as active/nonactive or toxic/nontoxic. To train a classifier, a training data set must consist of examples from both positive and negative classes. While a biological activity or toxicity can be experimentally measured, another important molecular property, a synthetic feasibility, is a more abstract feature that can’t be easily assessed. In the present paper, we introduce Nonpher, a computational method for the construction of a hard-to-synthesize virtual library. Nonpher is based on a molecular morphing algorithm in which new structures are iteratively generated by simple structural changes, such as the addition or removal of an atom or a bond. In Nonpher, molecular morphing was optimized so that it yields structures not overly complex, but just right hard-to-synthesize. Nonpher results were compared with SAscore and dense region (DR), other two methods for the generation of hard-to-synthesize compounds. Random forest classifier trained on Nonpher data achieves better results than models obtained using SAscore and DR data.

Chemo-enzymatic modification of eukaryotic mRNA.

Messenger RNA may not be very abundant in the cell but its central role in gene expression is indisputable. In addition to being the template for translation it can be subject for a variety of regulatory mechanisms affecting gene expression, ranging from simple structural changes to modifications and active transport. To elucidate and potentially control the underlying changes in vitro and in cells, site-specific modification and labeling strategies are required. In this perspective, we introduce chemo-enzymatic concepts for posttranscriptional modification focusing on eukaryotic mRNAs. We describe how eukaryotic mRNA can be enzymatically modified via its 5' cap. Directions towards chemo-enzymatic mRNA labeling and visualization inside cells are given, taking into account current developments in fluorophore design. Recent achievements and future perspectives will be highlighted in the framework of an honest discussion of existing challenges.

The Sulfur–FluorineGaucheEffect in Coinage-Metal Complexes: Augmenting Conformational Equilibria by Complexation

Controlling the rotation about unhindered C(sp3)–C(sp3) bonds by simple structural changes has obvious benefits in molecular design. While the avoidance of nonbonding interactions remains one of the cornerstones of acyclic conformational control, stabilizing stereoelectronic effects have the added benefit that conformer populations can be fine-tuned by augmenting or diminishing the central interaction. Strategies may include adjusting the oxidation state of a substituent or reversible formation of a complex to modulate MO levels. In the case of the sulfur–fluorine gauche effect, the propensity of the S–C–C–F motif to adopt a synclinal arrangement (ΦFCCS = 60°), the conformer population distribution of the three dominant rotamers partitioned by 120° can be biased by oxidation of the S atom. Motivated by the importance of sulfur-based ligands in main structural chemistry, the sulfur–fluorine gauche effect was translated to an organometallic paradigm as a potential tool to achieve structural preorganization. This would allow the influence of coinage-metal complexation on conformer population to be initially assessed. The synthesis and characterization of a model gold(I) and silver(I) metal complex featuring a ligand system containing a freely rotatable SCCF motif is disclosed. In both complexes, the title stereoelectronic effect manifests itself in the expected conformation, with the synclinal-endo conformer being preferred. This was corroborated by X-ray crystallography and DFT analysis, and the molar fraction of rotamers was extrapolated from a detailed solution-phase NMR spectroscopic analysis. Complexation was found to reinforce the sulfur–fluorine gauche effect.

Iron-Catalyzed Hydroboration: Unlocking Reactivity through Ligand Modulation.

Iron-catalyzed hydroboration (HB) of alkenes and alkynes is reported. A simple change in ligand structure leads to an extensive change in catalyst activity. Reactions proceed efficiently over a wide range of challenging substrates including activated, unactivated and sterically encumbered motifs. Conditions are mild and do not require the use of reducing agents or other additives. Large excesses of borating reagent are not required, allowing control of chemo- and regioselectivity in the presence of multiple double bonds. Mechanistic insight reveals that the reaction is likely to proceed via a highly reactive iron hydride intermediate.

The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors

The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.

Improved Tests for Forecast Comparisons in the Presence of Instabilities

Of interest is comparing the out‐of‐sample forecasting performance of two competing models in the presence of possible instabilities. To that effect, we suggest using simple structural change tests, sup‐Wald and UDmax for changes in the mean of the loss differences. It is shown that Giacomini and Rossi () tests have undesirable power properties, power that can be low and non‐increasing as the alternative becomes further from the null hypothesis. On the contrary, our statistics are shown to have higher monotonic power, especially the UDmax version. We use their empirical examples to show the practical relevance of the issues raised.

Analysis and perturbation of degree correlation in complex networks

Degree correlation is an important topological property common to many real-world networks such as the protein-protein interactions and the metabolic networks. In the letter, the statistical measures for characterizing the degree correlation in networks are investigated analytically. We give an exact proof of the consistency for the statistical measures, and reveal the general linear relation in the degree correlation, which provides a simple and interesting perspective on the analysis of the degree correlation in complex networks. By using the general linear analysis, we investigate the perturbation of the degree correlation in complex networks caused by the simple structural variation such as the “rich club”. The results show that the assortativity of homogeneous networks such as the Erdős-Rényi graphs is easily strongly affected by the simple structural changes, while it has only a slight variation for heterogeneous networks with broad degree distribution such as the scale-free networks. Clearly, the homogeneous networks are more sensitive to the perturbation than the heterogeneous networks.

Signal amplification in a microfluidic paper-based analytical device (µ-PAD) by confinement of the fluidic flow

This is a one-step POC biosensor that guarantees rapid assay times, low-cost analysis, simple handling, stability, and is easy to mass product. However, it has several drawbacks such as limited sample volume and relatively low sensitivity. To overcome these disadvantages, we have designed and fabricated the µ-PAD to confine fluid flow by creating a hydrophobic channel in the paper to improve the sensitivity. The channel pattern was drawn by a computer-aided design program and directly printed by a commercially available wax printer which generates the hydrophobic channel pattern. While maintaining a constant sample, absorption, and conjugation pad, the width of the detection pad was reduced from 5 mm to 2 mm at intervals of 1 mm. The intensity of bands from the single- and double-orifice patterns increased identically compared with the device with no orifice. The relative intensity of the signal bands increased from 141 to 158. Also, numerical simulation was performed to validate the experimental result by using lattice Boltzmann method. We observed that the sensitivity was enhanced at a specific detection pad width (3 mm). Therefore, our simple structural change of the channel led to improve the colorimetric intensity. Cortisol, which is a known stress biomarker, was used to validation the device, an enhanced signal was obtained indicating that our device can be used for the detection psychological stress in humans.

Functional Group-Dependent Self-Assembled Nanostructures from Thermo-Responsive Triblock Copolymers

The ability to control the formation of nanostructures through self-assembly of amphiphilic block copolymers is of great interest in the field of biology and catalysis. In this work we have studied the self-assembling behavior of a new class of thermo-responsive triblock copolymers containing poly(ethylene glycol), and demonstrated the manner in which the aggregation pattern changed on simple functional group transformation on the copolymers. Two different triblock copolymers, poly(ethylene glycol)-b-poly(N-ispropylacrylamide)-b-poly(t-butyl acrylate) (P1) and poly(ethylene glycol)-b-poly(N-isopropylacrylamide)-b-poly(glycidyl methacrylate) (P2) were synthesized using reversible addition-fragmentation chain transfer (RAFT) technique. It was observed that P1 and P2 displayed different temperature dependent solution properties in water, with P1 forming micelles above the LCST of the PNIPA while P2 showing macroscopic phase separation under similar conditions. Thereafter, the tert-butyl group of P1 was converted to the corresponding acid (P1a) and the epoxy groups of P2 was converted to diols (P2a), thus transforming the hydrophobic blocks to hydrophilic ones. Quite interestingly, such transformations led to significant changes in their self-assembling behavior, as both P1a and P2a were seen to form vesicles beyond the LCST of PNIPA. Changes in the hydrophilic fraction in the block copolymers by subtle changes in the functionality and temperature led to the formation of varied nanostructured assemblies, as evident from dynamic light scattering (DLS), transmisison electron microscopy (TEM), and steady-state fluorescence analysis. Such formation of thermo-responsive vesicles induced by simple structural changes in the copolymers is quite interesting and highly significant in drug delivery applications.

Molpher: a software framework for systematic chemical space exploration

BackgroundChemical space is virtual space occupied by all chemically meaningful organic compounds. It is an important concept in contemporary chemoinformatics research, and its systematic exploration is vital to the discovery of either novel drugs or new tools for chemical biology.ResultsIn this paper, we describe Molpher, an open-source framework for the systematic exploration of chemical space. Through a process we term ‘molecular morphing’, Molpher produces a path of structurally-related compounds. This path is generated by the iterative application of so-called ‘morphing operators’ that represent simple structural changes, such as the addition or removal of an atom or a bond. Molpher incorporates an optimized parallel exploration algorithm, compound logging and a two-dimensional visualization of the exploration process. Its feature set can be easily extended by implementing additional morphing operators, chemical fingerprints, similarity measures and visualization methods. Molpher not only offers an intuitive graphical user interface, but also can be run in batch mode. This enables users to easily incorporate molecular morphing into their existing drug discovery pipelines.ConclusionsMolpher is an open-source software framework for the design of virtual chemical libraries focused on a particular mechanistic class of compounds. These libraries, represented by a morphing path and its surroundings, provide valuable starting data for future in silico and in vitro experiments. Molpher is highly extensible and can be easily incorporated into any existing computational drug design pipeline.

Computer aided screening of Accacia nilotica phytochemicals against HCV NS3/4a.

Background: HCV has become a leading cause of liver cirrhosis and hepatocellular carcinoma and is a major health concern worldwide. To date, there is no vaccine available in the market to tackle this disease, therefore there is a strong need to develop antiviral compounds that can target all genotypes of HCV with the same efficiency. Medicinal plants have low cost and are less toxic therefore, extracts of medicinal plants can serve as important antiviral agents against HCV. This study was designed to screen phytochemicals of Accacia nilotica to find a potent drug candidate that can inhibit HCV infection effectively.Results: Docking of NS3/4A protease and Flavonoids of Accacia nilotica revealed that most of the flavonoids bound deeply with the active site of NS3/4A protease. Compound 01 showed a high ranking on docking score. All other compounds also showed reliable docking scores and had interactions with the binding cavity of NS3/4A protease, suggesting them as a potent drug candidate to block HCV replication.Conclusion: To recognize binding interactions of Accacia nilotica phytochemicals with NS3/4A protease, molecular docking was performed to find potential inhibitor against NS3/4A protease of HCV. After post docking analysis, important interactions were found between active compounds and active site of NS3/4A protease. It can be concluded from the study that phytochemicals of Accacia nilotica may serve as a potential drug candidate with relatively simple structural changes against HCV NS3/4A protease.

A strategy for disentangling the conductivity–stability dilemma in alkaline polymer electrolytes

Alkaline polymer electrolytes (APEs) are a new class of polyelectrolytes enabling the use of nonprecious metal catalysts in electrochemical devices, such as fuel cells and water electrolyzers. However, the current development of APEs is facing a severe difficulty, the conductivity–stability dilemma. Specifically, to acquire high ionic conductivity, the polymer backbone has to be grafted with enough cationic functional groups, typically quaternary ammonium (–NR3+), but such a modification in structure has damaged the chemical inertness of the polymer backbone and induced degradation in an alkaline environment. Here we demonstrate a strategy for disentangling such a dilemma. To alleviate the damage to the polymer backbone, we reduce the grafting degree (GD) of functional groups, but design two cations on each grafted functional group so as to retain sufficient ion concentration. Such a seemingly simple change in structure has brought a notable effect in performance: not only can both high ionic conductivity and much improved chemical stability be achieved, but also the intermolecular interaction between polymer chains has thus been enhanced, rendering the resulting APE membrane much stronger in mechanical strength and highly anti-swelling in water even at 80 °C.

Protein Dynamics Studied with Ultrafast Two-Dimensional Infrared Vibrational Echo Spectroscopy

Proteins, enzymes, and other biological molecules undergo structural dynamics as an intrinsic part of their biological functions. While many biological processes occur on the millisecond, second, and even longer time scales, the fundamental structural dynamics that eventually give rise to such processes occur on much faster time scales. Many decades ago, chemical kineticists focused on the inverse of the reaction rate constant as the important time scale for a chemical reaction. However, through transition state theory and a vast amount of experimental evidence, we now know that the key events in a chemical reaction can involve structural fluctuations that take a system of reactants to its transition state, the crossing of a barrier, and the eventual relaxation to product states. Such dynamics occur on very fast time scales. Today researchers would like to investigate the fast structural fluctuations of biological molecules to gain an understanding of how biological processes proceed from simple structural changes in biomolecules to the final, complex biological function. The study of the fast structural dynamics of biological molecules requires experiments that operate on the appropriate time scales, and in this Account, we discuss the application of ultrafast two-dimensional infrared (2D IR) vibrational echo spectroscopy to the study of protein dynamics. The 2D IR vibrational echo experiment is akin to 2D NMR, but it operates on time scales many orders of magnitude faster. In the experiments, a particular vibrational oscillator serves as a vibrational dynamics probe. As the structure of the protein evolves in time, the structural changes are manifested as time-dependent changes in the frequency of the vibrational dynamics probe. The 2D IR vibrational echo experiments can track the vibrational frequency evolution, which we then relate to the time evolution of the protein structure. In particular, we measured protein substate interconversion for mutants of myoglobin using 2D IR chemical exchange spectroscopy and observed well-defined substate interconversion on a sub-100 ps time scale. In another study, we investigated the influence of binding five different substrates to the enzyme cytochrome P450(cam). The various substrates affect the enzyme dynamics differently, and the observed dynamics are correlated with the enzyme's selectivity of hydroxylation of the substrates and with the substrate binding affinity.

On the treatment of airline travelers in mathematical models.

The global spread of infectious diseases is facilitated by the ability of infected humans to travel thousands of miles in short time spans, rapidly transporting pathogens to distant locations. Mathematical models of the actual and potential spread of specific pathogens can assist public health planning in the case of such an event. Models should generally be parsimonious, but must consider all potentially important components of the system to the greatest extent possible. We demonstrate and discuss important assumptions relative to the parameterization and structural treatment of airline travel in mathematical models. Among other findings, we show that the most common structural treatment of travelers leads to underestimation of the speed of spread and that connecting travel is critical to a realistic spread pattern. Models involving travelers can be improved significantly by relatively simple structural changes but also may require further attention to details of parameterization.