High Structural Diversity Research Articles

Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands.

Opioid ligands are a large group of G-protein-coupled receptor ligands possessing high structural diversity, along with complicated structure–activity relationships (SARs). To better understand their structural correlations as well as the related SARs, we developed the innovative template-based alignment modeling in our recent studies on a variety of opioid ligands. As previously reported, this approach showed promise but also with limitations, which was mainly attributed to the small size of morphine as a template. With this study, we set out to construct an artificial μ-agonist template to overcome this limitation. The newly constructed template contained a largely extended scaffold, along with a few special μ-features relevant to the μ-selectivity of opioid ligands. As demonstrated in this paper, the new template showed significantly improved efficacy in facilitating the alignment modeling of a wide variety of opioid ligands. This report comprises of two main parts. Part 1 discusses the general construction process and the structural features as well as a few typical examples of the template applications and Part 2 focuses on the template refinement and validation.

New strategy for identifying potential natural HIV-1 non-nucleoside reverse transcriptase inhibitors against drug-resistance: an in silico study

Non-nucleosides reverse transcriptase inhibitors (NNRTIs), specifically targeting the HIV-1 reverse transcriptase (RT), play a unique role in anti-AIDS agents due to their high antiviral potency, structural diversity, and low toxicity in antiretroviral combination therapies used to treat HIV. However, due to the emergence of new drug-resistant strains, the development of novel NNRTIs with adequate potency, improved resistance profiles and less toxicity is highly required. In this work, a novel virtual screening strategy combined with structure-based drug design was proposed to discover the potential inhibitors against drug-resistant HIV strains. Seven structure-variant RTs, ranging from the wild type to a hypothetical multi-mutant were regarded as target proteins to perform structure-based virtual screening. Totally 23 small molecules with good binding affinity were identified from the Traditional Chinese Medicine database (TCM) as potential NNRTIs candidates. Among these hits, (+)-Hinokinin has confirmed anti-HIV activity, and some hits are structurally identical with anti-HIV compounds. Almost all these hits are consistent with external experimental results. Molecular simulations analysis revealed that top 2 hits (Pallidisetin A and Pallidisetin B) bind stably and in high affinity to HIV-RT, which are ready to be experimental confirmed. These results suggested that the strategy we proposed is feasible, trustworthy and effective. Our finding might be helpful in the identification of novel NNRTIs against drug-resistant, and also provide a new clue for the discovery of HIV drugs in natural products.Communicated by Ramaswamy H. Sarma.

Identification of Novel Antibacterials Using Machine Learning Techniques.

Many pharmaceutical companies are avoiding the development of novel antibacterials due to a range of rational reasons and the high risk of failure. However, there is an urgent need for novel antibiotics especially against resistant bacterial strains. Available in silico models suffer from many drawbacks and, therefore, are not applicable for scoring novel molecules with high structural diversity by their antibacterial potency. Considering this, the overall aim of this study was to develop an efficient in silico model able to find compounds that have plenty of chances to exhibit antibacterial activity. Based on a proprietary screening campaign, we have accumulated a representative dataset of more than 140,000 molecules with antibacterial activity against Escherichia coli assessed in the same assay and under the same conditions. This intriguing set has no analogue in the scientific literature. We applied six in silico techniques to mine these data. For external validation, we used 5,000 compounds with low similarity towards training samples. The antibacterial activity of the selected molecules against E. coli was assessed using a comprehensive biological study. Kohonen-based nonlinear mapping was used for the first time and provided the best predictive power (av. 75.5%). Several compounds showed an outstanding antibacterial potency and were identified as translation machinery inhibitors in vitro and in vivo. For the best compounds, MIC and CC50 values were determined to allow us to estimate a selectivity index (SI). Many active compounds have a robust IP position.

Procyanidin B2 3″-O-gallate Isolated from Reynoutria elliptica Prevents Glutamate-Induced HT22 Cell Death by Blocking the Accumulation of Intracellular Reactive Oxygen Species.

In this study, we examined the neuroprotective effects of MeOH extract and bioactive compounds obtained from Reynoutria elliptica seeds using HT22 cells from the murine hippocampal cell line as its underlying molecular basis, which has not yet been elucidated. Our study showed that the MeOH extract of R. elliptica seeds strongly protected HT22 cells from glutamate toxicity. To clarify the responsible compound for the neuroprotective effects, we took an interest in procyanidins of R. elliptica since procyanidins are known to exhibit high structural diversity and neuroprotective activity. To isolate the procyanidins efficiently, a phytochemical investigation of the MeOH extract from R. elliptica seeds using the LC/MS-guided isolation approach was applied, and procyanidin B2 3″-O-gallate (1) was successfully isolated. The structure of 1 was elucidated by analyzing the nuclear magnetic resonance spectroscopic data and LC/MS analysis. The neuroprotective activities of 1 were thoroughly examined using HT22 cells. Compound 1 exhibited a strong antioxidant efficacy and blocked glutamate-mediated increase in the reactive oxygen species (ROS) accumulation. Furthermore, compound 1 significantly inhibited the phosphorylation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase, which were increased by glutamate. These findings prove that the extract of R. elliptica seeds containing procyanidin B2 3″-O-gallate, which is a strong neuroprotective component, can be used as a functional food forattenuating and regulating neurological disorders.

Molecular Evolution of Extensively Drug-Resistant (XDR) Pseudomonas aeruginosa Strains From Patients and Hospital Environment in a Prolonged Outbreak.

In this study, we aimed to elucidate a prolonged outbreak of extensively drug-resistant (XDR) Pseudomonas aeruginosa, at two adjacent hospitals over a time course of 4 years. Since all strains exhibited a similar antibiotic susceptibility pattern and carried the carbapenemase gene blaVIM, a monoclonal outbreak was assumed. To shed light on the intra-hospital evolution of these strains over time, whole genome sequence (WGS) analysis of 100 clinical and environmental outbreak strains was employed. Phylogenetic analysis of the core genome revealed the outbreak to be polyclonal, rather than monoclonal as initially suggested. The vast majority of strains fell into one of two major clusters, composed of 27 and 59 strains, and their accessory genome each revealed over 400 and 600 accessory genes, respectively, thus indicating an unexpectedly high structural diversity among phylogenetically clustered strains. Further analyses focused on the cluster with 59 strains, representing the hospital from which both clinical and environmental strains were available. Our investigation clearly shows both accumulation and loss of genes occur very frequently over time, as reflected by analysis of protein enrichment as well as functional enrichment. In addition, we investigated adaptation through single nucleotide polymorphisms (SNPs). Among the genes affected by SNPs, there are a multidrug efflux pump (mexZ) and a mercury detoxification operon (merR) with deleterious mutations, potentially leading to loss of repression with resistance against antibiotics and disinfectants. Our results not only confirm WGS to be a powerful tool for epidemiologic analyses, but also provide insights into molecular evolution during an XDR P. aeruginosa hospital outbreak. Genome mutation unveiled a striking genetic plasticity on an unexpectedly high level, mostly driven by horizontal gene transfer. Our study adds valuable information to the molecular understanding of “real-world” Intra-hospital P. aeruginosa evolution and is a step forward toward more personalized medicine in infection control.

Retrotransposons in Plant Genomes: Structure, Identification, and Classification through Bioinformatics and Machine Learning.

Transposable elements (TEs) are genomic units able to move within the genome of virtually all organisms. Due to their natural repetitive numbers and their high structural diversity, the identification and classification of TEs remain a challenge in sequenced genomes. Although TEs were initially regarded as “junk DNA”, it has been demonstrated that they play key roles in chromosome structures, gene expression, and regulation, as well as adaptation and evolution. A highly reliable annotation of these elements is, therefore, crucial to better understand genome functions and their evolution. To date, much bioinformatics software has been developed to address TE detection and classification processes, but many problematic aspects remain, such as the reliability, precision, and speed of the analyses. Machine learning and deep learning are algorithms that can make automatic predictions and decisions in a wide variety of scientific applications. They have been tested in bioinformatics and, more specifically for TEs, classification with encouraging results. In this review, we will discuss important aspects of TEs, such as their structure, importance in the evolution and architecture of the host, and their current classifications and nomenclatures. We will also address current methods and their limitations in identifying and classifying TEs.

N‐Heterocyclic Carbene/Copper Cooperative Catalysis for the Asymmetric Synthesis of Spirooxindoles

AbstractHighly enantioselective [3+3] and [3+4] annulations of isatin‐derived enals with ethynylethylene carbonates and ethynyl benzoxazinanones are enabled by NHC/cooper cooperative catalysis, leading to a big library of spirooxindole derivatives in high structural diversity and enantioselectivity (up to 99 % ee). Both reactions represent a nicely synergistic integration of NHC and copper catalysis, in which both catalysts activate the substrates and the chiral NHC perfectly controls the stereochemistry.

N-Heterocyclic Carbene/Copper Cooperative Catalysis for the Asymmetric Synthesis of Spirooxindoles.

Highly enantioselective [3+3] and [3+4] annulations of isatin-derived enals with ethynylethylene carbonates and ethynyl benzoxazinanones are enabled by NHC/cooper cooperative catalysis, leading to a big library of spirooxindole derivatives in high structural diversity and enantioselectivity (up to 99 % ee). Both reactions represent a nicely synergistic integration of NHC and copper catalysis, in which both catalysts activate the substrates and the chiral NHC perfectly controls the stereochemistry.

Potent and selective inhibitors for M32 metallocarboxypeptidases identified from high-throughput screening of anti-kinetoplastid chemical boxes.

Enzymes of the M32 family are Zn-dependent metallocarboxypeptidases (MCPs) widely distributed among prokaryotic organisms and just a few eukaryotes including Trypanosoma brucei and Trypanosoma cruzi, the causative agents of sleeping sickness and Chagas disease, respectively. These enzymes are absent in humans and several functions have been proposed for trypanosomatid M32 MCPs. However, no synthetic inhibitors have been reported so far for these enzymes. Here, we present the identification of a set of inhibitors for TcMCP-1 and TbMCP-1 (two trypanosomatid M32 enzymes sharing 71% protein sequence identity) from the GlaxoSmithKline HAT and CHAGAS chemical boxes; two collections grouping 404 compounds with high antiparasitic potency, drug-likeness, structural diversity and scientific novelty. For this purpose, we adapted continuous fluorescent enzymatic assays to a medium-throughput format and carried out the screening of both collections, followed by the construction of dose-response curves for the most promising hits. As a result, 30 micromolar-range inhibitors were discovered for one or both enzymes. The best hit, TCMDC-143620, showed sub-micromolar affinity for TcMCP-1, inhibited TbMCP-1 in the low micromolar range and was inactive against angiotensin I-converting enzyme (ACE), a potential mammalian off-target structurally related to M32 MCPs. This is the first inhibitor reported for this family of MCPs and considering its potency and specificity, TCMDC-143620 seems to be a promissory starting point to develop more specific and potent chemical tools targeting M32 MCPs from trypanosomatid parasites.

Floral species richness, structural diversity and conservation value of vanilla agroecosystems in Madagascar

AbstractAgricultural landscapes provide financial livelihoods for farming communities in rural areas. However, such agroenvironments can significantly impact the local floral biodiversity and introduce harmful invasive species to the ecosystem. Despite the prominence of plantations throughout the tropics, their effects on local flora are limited to only a few specific cash crops and geographical regions. Here, we compared the species richness and structural diversity of vegetation in natural forest fragments and three types of vanilla plantation within the Sava region of north‐east Madagascar ranging from those within or adjacent to existing forests, to intensively cultivated plantations. We recorded data on plant species abundance, diameter at breast height and canopy cover within multiple sites of each habitat. We used abundance data to calculate species richness indices, and we compared these metrics between habitats. Forested habitats contained a significantly higher floral species richness, structural diversity and more endemic and regionally native species than nonforested, anthropogenic vanilla plantations. However, our results suggest that the high floral species richness and structural diversity of natural forests can be partially achieved in vanilla plantations, depending on the site's management regime; traditionally managed vanilla plantations located close to natural forests can support diverse floral communities. These encouraging findings for plant conservation and sustainable agroforestry in Madagascar suggest that that newly created vanilla plantations and already existing nonforested plantations should endeavour to follow the more traditional forested approach to enhance the future sustainability and promote floristic diversity.

Marine Biosurfactants: Biosynthesis, Structural Diversity and Biotechnological Applications.

Biosurfactants are amphiphilic secondary metabolites produced by microorganisms. Marine bacteria have recently emerged as a rich source for these natural products which exhibit surface-active properties, making them useful for diverse applications such as detergents, wetting and foaming agents, solubilisers, emulsifiers and dispersants. Although precise structural data are often lacking, the already available information deduced from biochemical analyses and genome sequences of marine microbes indicates a high structural diversity including a broad spectrum of fatty acid derivatives, lipoamino acids, lipopeptides and glycolipids. This review aims to summarise biosyntheses and structures with an emphasis on low molecular weight biosurfactants produced by marine microorganisms and describes various biotechnological applications with special emphasis on their role in the bioremediation of oil-contaminated environments. Furthermore, novel exploitation strategies are suggested in an attempt to extend the existing biosurfactant portfolio.

Smart Materials by Nanoscale Magnetic Assembly

AbstractMagnetic assembly at the nanoscale level holds great potential for producing smart materials with high functional and structural diversity. Generally, the chemical, physical, and mechanical properties of the resulting materials can be engineered or dynamically tuned by controlling external magnetic fields. This Review analyzes the recent research progress on nanoscale magnetic assembly approaches toward the development of smart materials. The magnetic interactions between nanoparticles (both magnetic and nonmagnetic) and the interactions between nanoparticles and external magnetic fields are fully expatiated based on numerical simulations. In particular, the advancements of nanoscale magnetic assembly in responsive optical nanostructures, shape‐morphing systems, and advanced materials with tunable surface properties are introduced in three subsections. The key roles of magnetic interactions in nanoscale assembly toward customizable physical and chemical properties are highlighted, with focus on how to enable direct manipulation of the positional and orientational orders of the building blocks and orientational control of soft matrices through the incorporation of anisotropic magnetic structures.

Macrocyclic Diterpenoids from Euphorbiaceae as A Source of Potent and Selective Inhibitors of Chikungunya Virus Replication

Macrocyclic diterpenoids produced by plants of the Euphorbiaceae family are of considerable interest due to their high structural diversity; and their therapeutically relevant biological properties. Over the last decade many studies have reported the ability of macrocyclic diterpenoids to inhibit in cellulo the cytopathic effect induced by the chikungunya virus. This review; which covers the years 2011 to 2019; lists all macrocyclic diterpenoids that have been evaluated for their ability to inhibit viral replication. The structure–activity relationships and the probable involvement of protein kinase C in their mechanism of action are also detailed.

Rottlerin is a pan phosphodiesterase inhibitor and can induce neurodifferentiation in IMR-32 human neuroblastoma cells

Phosphodiesterases are promising targets for pharmacological intervention against various diseases. There are already inhibitors of PDE3, PDE4 and PDE5 as approved drugs. However there is an unmet need to discover new chemical scaffolds as PDE inhibitors. The main drawback of most of PDE inhibitors is their non specificity; owing to their structural resemblance to cAMP or cGMP. Natural product compounds offer high structural diversity hence may provide new PDE inhibitors. We decided to screen our institutional natural product compound library of nearly 900 molecules for PDE5 inhibition and explore the selectivity against PDE1-11 and cytotoxicity of the hit molecule/s. Rottlerin was identified as a PDE5 inhibitor. It was found to inhibit other PDEs with varying specificities. Structure activity relationship data and molecular dynamics studies showed that Tyr612, Asp764, Gln817 and Phe820 in the binding pocket of PDE5 play an important role in the activity of rottlerin. As a pan PDE inhibitor, rottlerin was also found to activate the AMPK pathway and induce neurodifferentiation in IMR-32 cells, with the effect more efficient in samples co-treated with cAMP activator Forskolin. Rottlerin at higher concentrations was shown to induce autophagy, apoptosis and G2/S cell cycle arrest in IMR-32 cells.

A Robust Machine Learning Algorithm for the Prediction of Methane Adsorption in Nanoporous Materials.

In the present study, we propose a new set of descriptors that, along with a few structural features of nanoporous materials, can be used by machine learning algorithms for accurate predictions of the gas uptake capacities of these materials. All new descriptors closely resemble the helium atom void fraction of the material framework. However, instead of a helium atom, a particle with an appropriately defined van der Waals radius is used. The set of void fractions of a small number of these particles is found to be sufficient to characterize uniquely the structure of each material and to account for the most important topological features. We assess the accuracy of our approach by examining the predictions of the random forest algorithm in the relative small dataset of the computation-ready, experimental (CoRE) MOFs (∼4700 structures) that have been experimentally synthesized and whose geometrical/structural features have been accurately calculated before. We first performed grand canonical Monte Carlo simulations to accurately determine their methane uptake capacities at two different temperatures (280 and 298 K) and three different pressures (1, 5.8, and 65 bar). Despite the high chemical and structural diversity of the CoRE MOFs, it was found that the use of the proposed descriptors significantly improves the accuracy of the machine learning algorithm, particularly at low pressures, compared to the predictions made based solely on the rest structural features. More importantly, the algorithm can be easily adapted for other types of nanoporous materials beyond MOFs. Convergence of the predictions was reached even for small training set sizes compared to what was found in previous works using the hypothetical MOF database.

Heterocycle Synthesis through Pd‐Catalyzed Carbonylative Coupling

Heterocyclic chemistry is one of the most important and attractive areas of organic chemistry. It involves the preparation of compounds endowed with very high structural diversity and plays a central role in a multitude of highly developed areas: fine chemicals, drugs, flavors, dyes, engineered materials, and many other kinds of products contain at least one heterocyclic ring in their molecular structure. Therefore, the discovery of new methods for heterocycle synthesis is a significant objective of modern organic chemists, especially if prepared in environmentally benign and synthetically efficient ways. In this context, this minireview focuses on the synergy of two green strategies, namely multicomponent reactions and palladium‐catalyzed carbonylations, for the construction of a wide variety of heterocyclic systems. These processes are of considerable interest because they combine synthetic efficiency with respect for the environment.

Intragenomic heterogeneity of intergenic ribosomal DNA spacers in Cucurbita moschata is determined by DNA minisatellites with variable potential to form non-canonical DNA conformations.

The intergenic spacer (IGS) of rDNA is frequently built of long blocks of tandem repeats. To estimate the intragenomic variability of such knotty regions, we employed PacBio sequencing of the Cucurbita moschata genome, in which thousands of rDNA copies are distributed across a number of loci. The rRNA coding regions are highly conserved, indicating intensive interlocus homogenization and/or high selection pressure. However, the IGS exhibits high intragenomic structural diversity. Two repeated blocks, R1 (300–1250 bp) and R2 (290–643 bp), account for most of the IGS variation. They exhibit minisatellite-like features built of multiple periodically spaced short GC-rich sequence motifs with the potential to adopt non-canonical DNA conformations, G-quadruplex-folded and left-handed Z-DNA. The mutual arrangement of these motifs can be used to classify IGS variants into five structural families. Subtle polymorphisms exist within each family due to a variable number of repeats, suggesting the coexistence of an enormous number of IGS variants. The substantial length and structural heterogeneity of IGS minisatellites suggests that the tempo of their divergence exceeds the tempo of the homogenization of rDNA arrays. As frequently occurring among plants, we hypothesize that their instability may influence transcription regulation and/or destabilize rDNA units, possibly spreading them across the genome.

Highly Modified Lanostane Triterpenes from Fruiting Bodies of the Basidiomycete Tomophagus sp.

Thirty-one highly modified lanostanes (1-31), together with 19 known compounds (32-50), were isolated from fruiting bodies of the wood-rot basidiomycete Tomophagus sp. The structures were elucidated by analyses of HRMS and NMR spectroscopic data. The present work demonstrates the high structural diversity of modified lanostane triterpenoids from Tomophagus. This paper also discusses structural revisions of several known derivatives. Some of the isolated compounds exhibited moderate antimalarial activity against Plasmodium falciparum K1 (IC50 5.1-19 μM).

MCR Scaffolds Get Hotter with 18F-Labeling.

Imaging techniques, such as positron emission tomography (PET), represent great progress in the clinical development of drugs and diagnostics. However, the efficient and timely synthesis of appropriately labeled compounds is a largely unsolved problem. Numerous small drug-like molecules with high structural diversity can be synthesized via convergent multicomponent reactions (MCRs). The combination of PET labeling with MCR synthesis of biologically active compounds can greatly simplify radioanalytical and imaging-based analysis. In a proof-of-concept study, we optimized robust on-site radiolabeling conditions that were subsequently applied to several structurally different drug-like MCR scaffolds (e.g., arenes, β-lactam, tetrazole, and oxazole). These labeled scaffolds were synthesized via pinacol-derived aryl boronic esters (arylBPin) by copper-mediated oxidative 18F-fluorination with radiochemical conversions (RCCs) from 15% to 76%.

Quantitative analysis of diverse sporomorph-derived sporopollenins

Over the years studies on sporopollenin have reported a wide variety of structures. However, the methods and techniques used to elucidate sporopollenin structures are highly diverse so that much is still unclear with respect to the nature and structural diversity of sporopollenins. In order to investigate the structural diversity in sporopollenin between different taxa, extant sporomorphs of ten different species ranging from a mushroom to a cycad were examined using a relatively simple and fast analytical procedure. Sporomorphs, before and after saponification, were analysed for sporopollenin composition by Thermally assisted Hydrolysis and Methylation (THM) using [13C]tetramethylammonium hydroxide ([13C]TMAH). The sporomorp chemical composition differed markedly between the groups of organisms analysed. Moreover, we not only identified the nature and relative quantities of the well-known sporopollenin constituents p-coumaric acid and ferulic acid but also many other phenolic moieties, such as caffeic acid, which appeared to be the most abundant phenolic constituent in spores of Equisetum palustre, Salvinia molesta, Cyrtomium falcatum and Anemia phyllitidis. Within the two Equisetum species analysed as well as in the closely related Azolla and Salvinia species the same suite of phenolic constituents were observed, but their relative distribution varied largely. We thus demonstrate the existence of a high structural diversity, both qualitatively and quantitatively in sporopollenins enabling future studies related to the evolution, phylogeny and (palaeo)environment of sporopollenin-producing organisms. Furthermore, a better knowledge of sporopollenin and its structural variety is of relevance to the rapidly growing application of spores and pollen as a drug delivery agent in medicine.