Study of Microstructure Change of Carbon Nanofibers as Binder-Free Anode for High-Performance Lithium-Ion Batteries

Flexible and binder-free film of N, O-doped carbon nanofibers (CNFs) is the ideal anode for high-energy-density batteries. Here, CNFs flexible films which the N, O dopant give defect in graphite structure results in high specific surface area more than 500 m2 g–1. A flexible film of CNF800 carbonized at 800 °C delivers initial capacities of 2000 and 755 mAh g–1 at the current densities of 5 and 10 A g–1, respectively. After 500 cycles, CNF800 remains the capacities of 1251, 865, 702, and 305 mAh g–1 at 0.5, 1, 5, and 10 A g–1, respectively. The microstructures of CNFs under various state of charge are studied by HRTEM, XPS, 13C NMR, and so forth. The lithiation/delithiation mainly happens to the interlayer of graphite domain of CNFs. The dopants of nitrogen and oxygen involve in lithiation, but much of LiN is irreversible. The excellent performances of CNFs film can be attributed to the N, O doped structure of graphite domain that has increased the conductivity and lithium storage ability. Further development of N, O doped CNFs may enable practical applications as flexible anode in high-performance lithium-ion batteries

Additional file 1 of Barriers to medication adherence in a rural-urban dual economy: a multi-stakeholder qualitative study

Additional file 1. Interview Guide

Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)–MYC Interaction

WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound 12 can disrupt WDR5–MYC interaction in cells and reduce MYC target gene expression. Our work provides useful probes to study WDR5–MYC interaction and its function in cancers, which can also be used as the starting point for further optimization toward drug-like small molecules

Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple processes. It is also a prominent target for pharmacological inhibition in diseases such as cancer, aging, and neurodegenerative disorders. Interactions between WDR5 and various partners are essential for sustaining its function. Most drug discovery efforts center on the WIN (WDR5 interaction motif) site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe the discovery of novel WDR5 inhibitors for the other WBM (WDR5 binding motif) pocket on this scaffold protein, to disrupt WDR5 interaction with its binding partner MYC by high-throughput biochemical screening, subsequent molecule optimization, and biological assessment. These new WDR5 inhibitors provide useful probes for future investigations of WDR5 and an avenue for targeting WDR5 as a therapeutic strategy

Data collection and statistics for the structure of EED -inhibitor complexes.

<p>Data collection and statistics for the structure of EED -inhibitor complexes.</p

Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED

<div><p>Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model. Here, we further report the identification and validation of four other EED binders along with EED162, the parental compound of EED226. The crystal structures for all these five compounds in complex with EED revealed a common deep pocket induced by the binding of this diverse set of compounds. This pocket was created after significant conformational rearrangement of the aromatic cage residues (Y365, Y148 and F97) in the H3K27me3 binding pocket of EED, the width of which was delineated by the side chains of these rearranged residues. In addition, all five compounds interact with the Arg367 at the bottom of the pocket. Each compound also displays unique features in its interaction with EED, suggesting the dynamics of the H3K27me3 pocket in accommodating the binding of different compounds. Our results provide structural insights for rational design of novel EED binder for the inhibition of PRC2 complex activity.</p></div

Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)–MYC Interaction

WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound 12 can disrupt WDR5–MYC interaction in cells and reduce MYC target gene expression. Our work provides useful probes to study WDR5–MYC interaction and its function in cancers, which can also be used as the starting point for further optimization toward drug-like small molecules

EED inhibitors compete with H3K27me3 peptide in both enzymatic and binding assays.

a. EED inhibitors compete with H3K27me3 in NCP based PRC2 enzymatic assays. The assay was carried out at 1 x and 10 x Kact for the stimulatory H3K27me3 peptide and the concentration of SAM and nucleosome were kept at Km. Inhibitors demonstrated significantly reduced potency at a higher concentration of H3K27me3 peptide. b. EED inhibitors compete with H3K27me3 in EED-H3K27me3 AlphaScreen binding assay (competition mode). All compounds reduced the AlphaScreen signal in a dose dependent-manner.</p

The crystal structures of H3K27me3 competitive inhibitors binding to EED.

<p><b>a.</b> Structures of EED-EZH2 peptide in complex with EED396, EED666, EED709, EED162 and EED210. The five structures are aligned and shown in the same view. The EZH2 peptide is highlighted as red cylinder. <b>b.</b> A representative highlight of the conformational change of Arg367, Trp364, and Tyr365, in comparison of the EED666 bound (Arg 367 in green, Tyr365 in blue, and Trp364 in red) in and H3K27me3 bound EED structures (top); below, comparison of EED666-bound EED pocket (right) with H3K27me3-bound pocket (left); EED is shown as a surface and colored white. H3K27me3 peptide is shown as ball-and-stick in green color; for clarity, only the surface of residues Arg367 (green), Tyr365 (blue) and Trp364(red) are highlighted. <b>c</b>. The dynamic conformational changes of Arg367, Tyr365, Tyr148 and Phe97 in inhibitor bound EED structures.</p

Identification of allosteric PRC2 inhibitors through EED binding.

<p><b>a.</b> Flowchart of EEDi identification and validation from PRC2 high throughput screening. <b>b.</b> Chemical structures of five identified SAM non-competitive inhibitors. The IC50 values were determined using an EED-H3K27me3 AlphaScreen competition binding assay.</p