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Fragmentation‐based methods for nuclear magnetic resonance (NMR) chemical shift calculations have become more and more popular in first‐principles calculations of large molecules. However, there are many options for a fragmentation‐based method to select, such as theoretical methods, fragmentation schemes, the number of levels of theory, etc. It is important to study the optimal combination of the options to achieve a good balance between accuracy and efficiency. Here we investigate different combinations of options used by a fragmentation‐based method, the eXtended ONIOM (XO) method, for 13C chemical shift calculations on a set of organic and biological molecules. We found that: (1) introducing Hartree‐Fock exchange into density functional theory (DFT) could reduce the calculation error due to fragmentation in contrast to pure DFT functionals, while a hybrid functional, xOPBE, is generally recommended; (2) fragmentation schemes generated from the molecular tailoring approach (MTA) with small level parameter n, for example, n = 2 and the degree‐based fragmentation method (DBFM) with n = 1, are sufficient to achieve satisfactory accuracy; (3) the two‐level XO (XO2) NMR calculation is superior to the calculation with only one level of theory, as the second level (i.e., low level) of theory provides a way to well describe the long‐range effect. These findings are beneficial to practical applications of fragmentation‐based methods for NMR chemical shift calculations of large molecules. [ABSTRACT FROM AUTHOR]

We report solid-state 13C NMR spectra of urea-loaded copper benzoate, Cu 2 (C 6 H 5 CO 2) 4 ·2(urea), a simplified model for copper paddlewheel-based metal-organic frameworks (MOFs), along with first-principles density functional theory (DFT) computation of the paramagnetic NMR (pNMR) chemical shifts. Assuming a Boltzmann distribution between a diamagnetic open-shell singlet ground state (in a broken-symmetry Kohn-Sham DFT description) and an excited triplet state, the observed δ (13C) values are reproduced reasonably well at the PBE0-⅓/IGLO-II//PBE0-D3/AE1 level. Using the proposed assignments of the signals, the mean absolute deviation between computed and observed 13C chemical shifts is below 30 ppm over a range of more than 1100 ppm. Image 1 • Cu(C 6 H 5 CO 2) 4 ·2(urea), a model for metal-organic frameworks, shows pNMR shifts for 13C. • The shifts stem from a triplet state in equilibrium with the singlet ground state. • Shifts are computed assuming a Boltzmann distribution of the two spin states. • Sign and magnitude of the pNMR shifts can be rationalised by the triplet spin density. [ABSTRACT FROM AUTHOR]

We present a strategy for predicting the unusual 1H and 13C shifts in NMR spectra of paramagnetic bisoximato copper(ii) complexes using DFT. We demonstrate good agreement with experimental measurements, although 1H–13C correlation spectra show that a combined experimental and theoretical approach remains necessary for full assignment. [ABSTRACT FROM AUTHOR]

Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates. [ABSTRACT FROM AUTHOR]

Post-modification approaches such as Li-doping, impregnation, and functionalization are promising methods to enhance H 2 adsorption in metal–organic frameworks (MOFs) and covalent-organic frameworks (COFs). In this work, we propose a two-step method to modify COF-108 with the aim to enhance its hydrogen storage capacity at ambient temperature. First, we geometrically modified COF-108 through C 60 impregnation or aromatic ring grafting. Subsequently, we surface doped the modified COF-108 with Li atoms. COF-108 is the lightest 3D crystalline material ever reported and it is a promising H 2 storage material. Our grand canonical Monte Carlo (GCMC) simulations demonstrated that the combination of Li-doping with C 60 impregnation or aromatic ring grafting can potentially increase the volumetric H 2 adsorption capacity of COF-108 to reach a total H 2 adsorption capacity close to the U.S. DOE target. One of the Li-doped C 60 -impregnated (Li 6 C 60 ) COF-108 (with 8 Li 6 C 60 moieties impregnated) showed an absolute H 2 uptake beyond the 2010 DOE target (45.6 mg/g and 28.6 g/cm 3 ) at 233 K and 100 bar. Impregnation of C 60 and/or grafting of aromatic rings not only increased the density of doped Li in the modified COF-108 but also created more overlapped potential interaction with H 2 , which resulted in higher number of H 2 adsorption sites per unit volume as compared to the unmodified material. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, referring to as the progressive loss of structure and function of neurons, constitute one of the major challenges of modern medicine. Traditional Chinese herbs have been used as a major preventive and therapeutic strategy against disease for thousands years. The numerous species of medicinal herbs and Traditional Chinese Medicine (TCM) compound formulas in nervous system disease therapy make it a large chemical resource library for drug discovery. In this work, we collected 7362 kinds of herbs and 58,147 Traditional Chinese medicinal compounds (Tcmcs). The predicted active compounds in herbs have good oral bioavailability and central nervous system (CNS) permeability. The molecular docking and network analysis were employed to analyze the effects of herbs on neurodegenerative diseases. In order to evaluate the predicted efficacy of herbs, automated text mining was utilized to exhaustively search in PubMed by some related keywords. After that, receiver operator characteristic (ROC) curves was used to estimate the accuracy of predictions. Our study suggested that most herbs were distributed in family of Asteraceae, Fabaceae, Lamiaceae and Apocynaceae. The predictive model yielded good sensitivity and specificity with the AUC values above 0.800. At last, 504 kinds of herbs were obtained by using the optimal cutoff values in ROC curves. These 504 herbs would be the most potential herb resources for neurodegenerative diseases treatment. This study would give us an opportunity to use these herbs as a chemical resource library for drug discovery of anti-neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Highlights: [•] We developed CoMFA, CoMSIA and Topomer CoMFA models for a series of ALK inhibitors. [•] Topomer Search was utilized for virtual screening to obtain suitable fragments. [•] Novel compounds were generated by molecular fragment replacement. [•] Novel compounds were evaluated by 3D-QSAR models prediction and docking analysis. [•] A set of novel derivatives with predicted activities were designed. [Copyright &y& Elsevier]

Luteoloside is a member of the flavonoids family that exhibits several bioactivities including anti-microbial and anti-cancer activities. However, the antiviral activity of luteoloside against enterovirus 71 (EV71) and the potential mechanism(s) responsible for this effect remain unknown. In this study, the antiviral potency of luteoloside against EV71 and its inhibitory effects on 3C protease activity were evaluated. First, we investigated the cytotoxicity of luteoloside against rhabdomyosarcoma (RD) cells, which was the cell line selected for an in vitro infection model. In a subsequent antiviral assay, the cytopathic effect of EV71 was significantly and dose-dependently relieved by the administration of luteoloside (EC50 = 0.43 mM, selection index = 5.3). Using a plaque reduction assay, we administered luteoloside at various time points and found that the compound reduced EV71 viability in RD cells rather than increasing defensive mobilization or viral absorption. Moreover, biochemical studies focused on VP1 (a key structural protein of EV71) mRNA transcript and protein levels also revealed the inhibitory effects of luteoloside on the EV71 viral yield. Finally, we performed inhibition assays using luteoloside to evaluate its effect on recombinant 3C protease activity. Our results demonstrated that luteoloside blocked 3C protease enzymatic activity in a dose-dependent manner (IC50 = 0.36 mM) that was similar to the effect of rutin, which is a well-known C3 protease inhibitor. Collectively, the results from this study indicate that luteoloside can block 3C protease activity and subsequently inhibit EV71 production in vitro. [ABSTRACT FROM AUTHOR]

Abstract: The surface enhanced Raman scattering of trititanate nanotubes (TiNT) modified with enediol ligands was investigated and it was found that the functional group dramatically affects the enhancement observed. For TiNT‐4‐nitrocatechol, a SERS enhancement is seen; however, when dopamine is attached, no signal is seen. The relative band gap positions upon 785 nm laser excitation are proposed to explain the observed phenomenon. This attachment is investigated by solid state NMR and UV/Vis spectroscopy and supported by DFT calculations to offers further insights into catechol coatings of nanomaterials and SERS by the chemical method. We expect this non noble metal containing composite material to have applications in bioimaging and bio and chemical detection. [ABSTRACT FROM AUTHOR]

San-Huang-Tang (SHT), a traditional Chinese medicine (TCM) formula, has been clinically used to treat obesity and type 2 diabetes mellitus. Recently it has proved that SHT have a good effect on non-alcoholic fatty liver disease (NAFLD). Our study was designed to investigate the therapeutic mechanisms of the SHT against NAFLD. The data of SHT were obtained through network pharmacology platform and validated experimentally in vivo and in vitro. The candidate targets of SHT were predicted by network pharmacological analysis and crucial targets were chosen by the protein-protein interaction (PPI) network. Furthermore, Gene Ontology (GO) and Kyoto encyclopedia of genes and Genomes (KEGG) were applied to analyze the NAFLD-related signaling pathways affected by SHT, and then the analysis results were verified with molecular biological experiments in vivo and in vitro. Molecules were screened with network pharmacological analysis, and then the improvement of insulin resistance of NAFLD mice was measured by IPITTs and IPGTTs. Through series of molecular experiments, it is revealed that SHT could increase the transcription of insulin receptor (INSR) and insulin receptor substrate (IRS1), and enhance the phosphorylation of both threonine protein kinase (AKT) and forkhead box O1 (FoxO1). Screened by bioinformatics and verified by experiments in vivo and in vitro , SHT could contribute to NAFLD by affecting insulin resistance via activating INSR/IRS1/AKT/FoxO1 pathway. Our research findings provide not only an experimental basis for the therapeutic effect of SHT but also a new target against NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

Fragment-based drug design has emerged as an important methodology for lead discovery and drug design. Different with other studies focused on fragment library design and active fragment identification, a fragment-based strategy was developed in combination with three-dimensional quantitative structure–activity relationship (3D-QSAR) for structural optimization in this study. Based on a validated scaffold or fragment hit, a series of structural optimization was conducted to convert it to lead compounds, including 3D-QSAR modelling, active site analysis, fragment-based structural optimization and evaluation of new molecules. 3D-QSAR models and active site analysis provided sufficient information for confirming the SAR and pharmacophoric features for fragments. This strategy was evaluated through the structural optimization on a c-Met inhibitor scaffold 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one, which resulted in an c-Met inhibitor with high inhibitory activity. Our study suggested the effectiveness of this fragment-based strategy and the druggability of our newly explored active region. The reliability of this strategy indicated it could also be applied to facilitate lead optimization of other targets. [ABSTRACT FROM AUTHOR]

• A strategy was provided to elucidate herbal interaction through manually EICs. • Herbal interaction of vSCF and ZSS was elucidated by above proposed strategy. • Due to co-decoction, JuA can be transformed into its ebelin lactone form. For characterizing the influence of vinegar processed Schisandrae Chinensis Fruit (vSCF) on the dissolution of constituents of Ziziphi spinosae Semen (ZSS) when co-decocted, a strategy for herbal interaction was currently proposed based on process route design of new drug of Chinese herbal formulae. Firstly, the content of jujuboside A (JuA) in ZSS-vSCF co-decoction was determined at different ratios by high performance liquid chromatography coupled with evaporative light-scattering detector (HPLC-ELSD), to demonstrate the influence of vSCF on JuA of ZSS. As the results showed, the content of JuA was declined drastically in ZSS-vSCF co-decoction compared to the ZSS single decoction, especially at the ratio of 1:1. Hence, the ratio of 1:1 was used in the following studies. Furtherly, as pre-extraction is usually taken in the pharmaceutical industry of Chinese patent medicines (CPM) to avoid herbal interaction, thus the pre-extracted solvents of vSCF were investigated. The content of JuA in coupled decoction was indeed improved when vSCF was pre-extracted before co-decocted with ZSS. Among the pre-extracted solvents, 60% ethanol possessed a better-improved effect. Therefore, 60% ethanol extract of vSCF was treated with JuA and the transformed compounds of JuA can be identified by ultra high performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS/MS). Then, we reported that jujubosides, the main saponins in ZSS, would be transformed into its ebelin-lactone forms through dehydration, RDA cleavage and hydrolysis of glycosidic bond, which could be induced by organic acid in vSCF. Additionally, to elucidate the comprehensive influence, 45 compounds were tentatively identified by UPLC–ESI-Q-TOF-MS/MS, and their dissolution variation in different ZSS-vSCF co-decoction was represented by manually acquired EICs, as well. It can be found that vSCF can promote extraction efficiencies of alkaloids and flavonoid O-glycosides of ZSS when co-decocted, while saponins were suppressed. Similarly, the pre-extraction of vSCF could reverse the suppression. To further elucidate the significance of ZSS-vSCF co-decoction, a comparison of molecular modeling between JuA and its ebelin-lactone form were carried out, revealing that the corresponding ebelin-lactone form had a stronger binding affinity than JuA toward calmodulin (CaM). Collectively, to lower the herbal interaction, a pre-extraction method was developed against the decrease of JuA in ZSS-vSCF co-decoction. And the dissolution of different types of constituents in ZSS was investigated by a semi-quantitative method, as well. Also, ebelin-lactone form of JuA, which resulted from ZSS-vSCF co-decoction, demonstrated a stronger binding affinity toward CaM in virtual screening, but the future pharmacological and pharmacokinetic research is worthy to be further studied. [ABSTRACT FROM AUTHOR]