Crystal Structure Of Complex Research Articles

Crystal structure of tubulin-barbigerone complex enables rational design of potent anticancer agents with isoflavone skeleton

BackgroundIsoflavones possess many biological activities, including anti-inflammatory and anticancer effects. Microtubules (composed of αβ-tubulin heterodimers) are described as one possible cellular target of some of these isoflavones. However, the binding of tubulin to isoflavones has not been extensively studied, and until now, no crystal structure of the tubulin-isoflavone complex has been solved, and details of the isoflavone-tubulin interaction remain elusive. PurposeBarbigerone is an isoflavone mainly found in the genus Milletti, such as the edible leguminous plant Millettia ferruginea, with anticancer activity. This study aims to confirm the cellular target of barbigerone and to study its anticancer mechanism. Method: Surface plasmon resonance assays and X-ray crystallography were used to study the interaction of barbigerone with tubulin protein. Immunofluorescence, in-cell and in vitro tubulin polymerization assays were employed to investigate the mechanism. MTT assays, cell clonal formation assays, wound healing assays, tube formation assays and H460 xenograft models were conducted to evaluate the in vitro and in vivo anticancer activities of barbigerone and one of its derivatives, 0412. ResultsHere, we found that barbigerone binds to tubulin to inhibit tubulin polymerization. Moreover, we solved the X-ray crystal structure of the tubulin-barbigerone complex at 2.33 Å resolution, which unambiguously determined the orientation and position of barbigerone in the colchicine-binding site. Illuminated by the X-ray data, we synthetized and obtained a more active isoflavone, 0412. Both barbigerone and 0412 inhibit cancer cell proliferation, tubulin polymerization, migration of HeLa cells and capillary-like tube formation of HUVECs, induce G2/M phase cell cycle arrest and apoptosis, and exhibit anticancer activity in an H460 xenograft model. ConclusionIn all, through biochemical and X-ray crystal structure results, we identified tubulin as the cellular target of one isoflavone, barbigerone, and proved that the tubulin-barbigerone complex plays a guiding role in obtaining a more active compound, 0412. These studies provide a crucial research basis for the development of isoflavones as anticancer candidate compounds.

Pyridyl-containing dialkylphosphine oxides and their chelate copper(II) complexes

Water-soluble copper(II) complexes based on novel phosphorylpyridines, namely, diethyl(pyridin-2-yl)phosphine oxide (3), diisopropyl(pyridin-2-yl)phosphine oxide (4) were obtained. The molecular and crystal structures of complexes were established by X-ray analysis. The cytotoxicity against M-HeLa and HuTu80 cancer cell lines and Chang liver normal cell lines was examined for all obtained ligands and complexes.

A Proton Conducting Cobalt(II) Spin Crossover Complex.

Spin crossover (SCO) complexes have been extensively explored as bistable materials and recently used as molecular modules for the development of new multifunctional molecular magnetic materials. Herein, we present the synthesis, crystal structure, magnetic, and electrical properties of a mononuclear cobalt complex constructed by a halogen-functionalized terpyridine derivative and organosulfonate. A complete and gradual spin transition with the T1/2 =200 K was observed for the Co2+ ions through both the magnetic measurement and dynamic crystallographic experiments. Interestingly, considerable room temperature proton conductivity of 6.9×10-5 S cm-1 under 98% relative humidity was evidenced because of the presence of sulfonate-assisted hydrogen-bonded proton hopping pathways. The forgoing results not only provide an unprecedented proton-conducting cobalt(II) SCO complex but also a promising way for the design and construction of bifunctional SCO molecular conductors via the incorporation of SCO transition and proton conduction.

Occurrence Characteristics of Fine-Grained Pyrite in Coal and Its Scaling Effect on Flotation Desulfurization.

To explore the occurrence and distribution characteristics of fine-grained pyrites in coal and the effect of pyrite particle size on flotation efficiency, coal samples from Guizhou province and Shanxi province, China, were selected for pyrite morphology observation and sulfur content test before and after flotation desulfurization experiments with different coal particle sizes. Experimental results showed that the fine-grained fine pyrites in coal have various occurrence forms and complex connections with the coal matrix. The fragmentation process can change the distribution of pyrite content in coal. Flotation desulfurization experiments showed that the sum of pyrite content in the cleaned coal and middlings gradually became significantly higher in coal particles with size 15-37 μm compared with particle sizes 37-44 and 44-75 μm. The complex occurrence morphology and crystal structure of fine-grained pyrite make it difficult to be removed from the coal matrix by ore grinding during flotation. Fine-grained pyrite mainly occurs in the form of framboïdal pyrite, disseminated pyrite, and monomer pyrite with a size of 0.69-33.94 μm in the middlings and cleaned coal. Therefore, 37 μm is considered as the critical dimension for ore grinding to improve the effective flotation desulphurization efficiency in this study, and some more effective methods should be used to increase the desulfurization efficiency of fine-grained pyrite.

Application of third-order nonlinear optical materials in complex crystalline chemical reactions of borates

Abstract In order to explore the application of third-order nonlinear optical (NLO) materials in complex borate crystalline chemical reactions, the laser light source with limited wavelength range can be extended to ultraviolet (UV) and deep UV region by using NLO crystal materials and frequency conversion technology, which has become a hot research direction of deep UV light source. The experimental results show that the UV cutoff edge of the grown KLi(HC3N3O3)·2H2O crystal is 237 nm. The refractive index of the crystal was measured by prism coupling technique, and the Sellmeier equation of the refractive index of the crystal was fitted. The chemical bond of the crystal is a fundamental means to understand the relationship between structure and properties. With the emergence of a large number of hybrid functional crystals, the composition and structure of crystals become more complex, and the chemical bond theory has also been greatly developed, and then the chemical bond theory of meta crystals or complex crystals has emerged. Once proposed, the theory has been widely used, such as analyzing the eligibility of luminescent crystals, NLO crystals and high-temperature superconductor crystals. NLO materials are the dominant field of China in the world. Crystals with good nonlinear behavior have more complex crystal structures, due to the theory of amorphous structure, the exploration of this aspect is particularly difficult. For the first time, the influence of the composition of rare earth-doped bismuth borate glass on the crystal precipitation and glass microstructure of NLO materials was systematically studied, which laid a theoretical foundation for further development and understanding of new bismuth borate optical systems.

Development of Fluorinated Peptoid-Based Histone Deacetylase (HDAC) Inhibitors for Therapy-Resistant Acute Leukemia.

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p, which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.

The binding affinity of human pediatric respiratory syncytial virus Phosphoprotein's C-terminal tail to nucleocapsid can be improved by a rationally designed halogen-bonded system

Human respiratory syncytial virus (hRSV) is a common contagious virus that causes infections of pediatric pneumonia and specifically impacts infants and small children. The hRSV phosphoprotein is a key component of the viral RNA polymerase, which can interact with nucleocapsid and other partners through its C-terminal tail (CTT) to promote the formation of viral transcriptase complex, where the Phe241 is a key anchor residue. Based on the crystal template-modeled complex structure of hRSV nucleocapsid with a peptidic segment derived from the phosphoprotein's CTT, we successfully introduced a rationally designed halogen-bonded system to the complex interface by substituting para (p)-position of the side-chain phenyl moiety of CTT Phe241 residue with a halogen atom X (X = F, Cl, Br or I). The halogen-bonded system consists of a halogen bond (X-bond) between nucleocapsid Ser131 residue and CTT Phe241 residue as well as a hydrogen bond (H-bond) between nucleocapsid Ser131 residue and nucleocapsid Glu128 residue; the X-bond and H-bond share a common hydroxyl group of nucleocapsid Ser131 residue. High-level theoretical calculations suggested that bromine Br is the best choice that can render strong potency for the X-bond and can confer high affinity to the nucleocapsid–CTT binding. Affinity analysis revealed that the p-brominated CTT ([p]bCTT) exhibited 6.3-fold affinity improvement relative to its nonhalogenated counterpart. In contrast, the Br-substitutions at ortho (o)- and meta (m)-positions, which resulted in two negative controls of o-brominated [o]bCTT and m-brominated [m]bCTT, respectively, were unable to form effective X-bond with nucleocapsid according to theoretical investigation and did not improve the binding affinity essentially relative to native CTT.

A novel allosteric site employs a conserved inhibition mechanism in human kidney-type glutaminase.

Glutaminase catalyses the metabolic process called glutaminolysis. Cancer cells harness glutaminolysis to increase energy reserves under stressful conditions for rapid proliferation. Glutaminases are upregulated in many tumours. In humans, the kidney-type glutaminase (KGA) isoform is highly expressed in the kidney, brain, intestine, foetal liver, lymphocytes and in many tumours. Glutaminase inhibition is shown to be effective in controlling cancers. Previously, we and others reported the inhibition mechanism of KGA using various inhibitors that target the active and allosteric sites of the enzyme. Here, we report the identification of a novel allosteric site in KGA using the compound DDP through its complex crystal structure combined with mutational and hydrogen-deuterium exchange mass spectrometry studies. This allosteric site is located at the dimer interface, situated ~ 31 Å away from the previously identified allosteric site and ~ 32 Å away from the active site. Remarkably, the mechanism of inhibition is conserved, irrespective of which allosteric pocket is targeted, causing the same conformational changes in the key loop near the active site (Glu312-Pro329) and subsequent enzyme inactivation. Contrary to the previously identified allosteric site, the identified new allosteric site is primarily hydrophilic. This site could be effectively targeted for the synthesis of specific and potent water-soluble inhibitors of glutaminase, which will lead to the development of anticancer drugs.

Novel Organotin(IV) Complexes of 2-[4-Hydroxy-3-((2-hydroxyethylimino)methyl)phenylazo]benzoic Acid: Synthesis, Structure, Noncovalent Interactions and In Vitro Antibacterial Activity

Three new organotin(IV) complexes, [Me3Sn(H2L)]2 (1), Bu3Sn(H2L) (2), and [(Bu2Sn(H2L))2O]2 (3) were synthesized by the reaction of 2-[4-hydroxy-3-((2-hydroxyethylimino)methyl)phenylazo]benzoic acid (H3L) with appropriate alkyltin(IV) precursors. The complexes were characterized by elemental analysis, IR, and multinuclear (1H, 13C and 119Sn) NMR spectroscopy. Further, the complex 1 was analyzed by single-crystal X-ray analysis. It displays a 24-membered cyclic dimeric Me3SnIV(H2L) unit where the ligand act as a bridging framework using its carboxylate-O and phenoxy-O atoms. The Sn(IV) adopts distorted trigonal-bipyramidal geometry. In the solution state, the structures were determined by 119Sn-NMR spectroscopy, and the complexes 1 and 2 have distorted tetrahedral geometry, whereas complex 3 shows distorted trigonal-bipyramidal geometry around the tin centres. The Hirshfeld surface analysis and DFT calculations, together with a topological analysis of the electron density distribution in the crystal structure of complex 1, indicate that its molecular packing determined by various noncovalent interactions, including stacking and hydrogen bonding. The antibacterial studies of the ligand and the complexes (1–3) against gram-negative bacteria viz. Klebsiella pneumoniae (A),Vibrio cholerae (M) and Shigella boydii (Q) and gram-positive bacteria viz.Staphylococcus aureus (J), Streptococcus pneumonia (K) are promising and the compounds can be treated as potential common antibacterial materials.

Cycloalkyl Groups as Building Blocks of Artificial Carbohydrate Receptors: Studies with Macrocycles Bearing Flexible Side-Arms.

The cyclopentyl group was expected to act as a building block for artificial carbohydrate receptors and to participate in van der Waals contacts with the carbohydrate substrate in a similar way as observed for the pyrrolidine ring of proline in the crystal structures of protein-carbohydrate complexes. Systematic binding studies with a series of 1,3,5-trisubstituted 2,4,6-triethylbenzenes bearing various cycloalkyl groups as recognition units provided indications of the involvement of these groups in the complexation process and showed the influence of the ring size on the receptor efficiency. Representatives of compounds that exhibit a macrocyclic backbone and flexible side arms were now chosen as further model systems to investigate whether the previously observed effects represent a general trend. Binding studies with these macrocycles towards β-D-glucopyranoside, an all-equatorial substituted carbohydrate substrate, included 1H NMR spectroscopic titrations and microcalorimetric investigations. The performed studies confirmed the previously observed tendency and showed that the compound bearing cyclohexyl groups displays the best binding properties.

Synthesis, Characterization, and Catalysis of Water‐Soluble Trimeric and Monomeric Palladium Complexes of 8‐Aminoquinolines

AbstractNew water soluble neutral and cationic palladium complexes were synthesized using 8‐aminoquinoline (8‐AQ) and 2‐methyl 8‐aminoquinoline (2‐Me 8‐AQ) ligands and their catalytic properties were evaluated. The neutral trimeric complexes having a Pd3N3 core were found to form when Pd(OAc)2 was reacted with 8‐AQ or 2‐Me 8‐AQ irrespective of the stoichiometry between the 2 reagents. Controlled addition of triflic acid to the neutral trimeric complex resulted in the formation of a trimeric cationic palladium complex as well as a monomeric cationic complex. A cationic palladium complex having two units of 2‐Me‐8AQ ligand was also synthesized from the cationic monomeric complex. Crystal structures of the new palladium complexes are reported in this study. The water‐soluble neutral palladium complex showed catalytic activity for the oxidation of benzyl alcohols to benzaldehydes, while the cationic palladium complexes were found to be efficient catalysts for the oxidation of styrenes to methyl ketones.

TotBlocks: exploring the relationships between modular rock-forming minerals with 3D-printed interlocking brick modules

Abstract. Many rock-forming chain and sheet silicate minerals, i.e., pyroxenes, amphiboles, micas, and clay minerals, are built from shared chemical building blocks known as T-O-T modules. Each module consists of two opposing chains of vertex-sharing silica tetrahedra (T), which vertically sandwich a ribbon of edge-sharing metal–oxygen octahedra (O) in a T-O-T configuration. These minerals are both abundant and diverse in the lithosphere because T-O-T modules are chemically versatile (incorporating common crustal elements, e.g., O, Si, Al, Fe, and Mg) and structurally versatile (varying as a function of module width and linkage type) over a wide range of chemical and physical conditions. Therefore, these minerals lie at the center of understanding geological processes. However, their diversity leads to the minerals developing complex, 3D crystal structures, which are challenging to communicate. Ball-and-stick models and computer visualization software are the current methods for communicating the crystal structures of minerals, but both methods have limitations in communicating the relationships between these complex crystal structures. Here, we investigate the applications of 3D printing in communicating modular mineralogy and crystal structures. The open-source TotBlocks project consists of 3D-printed, T-O-T interlocking bricks, based on ideal polyhedral representations of T and O modules, which are linked by hexagonal pegs and slots. Using TotBlocks, we explore the relationships between modular minerals within the biopyribole (biotite–pyroxene–amphibole) and palysepiole (palygorskite–sepiolite) series. The bricks can also be deconstructed into T and O layer modules to build other mineral structures such as the brucite, kaolinite–serpentine, and chlorite groups. Then, we use the T-O-T modules within these minerals to visually investigate trends in their properties, e.g., habit, cleavage angles, and symmetry/polytypism. In conclusion, the TotBlocks project provides an accessible, interactive, and versatile way to communicate the crystal structures of common rock-forming minerals.

Identification of small molecules as potential inhibitors of interleukin 6: a multi-computational investigation.

IL(interleukin)-6 is a multifunctional cytokine crucial for immunological, hematopoiesis, inflammation, and bone metabolism. Strikingly, IL-6 has been shown to significantly contribute to the initiation of cytokine storm-an acute systemic inflammatory syndrome in Covid-19 patients. Recent study has showed that blocking the IL-6 signaling pathway with an anti-IL-6 receptor monoclonal antibody (mAb) can reduce the severity of COVID-19 symptoms and enhance patient survival. However, the mAb has several drawbacks, such as high cost, potential immunogenicity, and invasive administration due to the large-molecule protein product. Instead, these issues could be mitigated using small molecule IL-6 inhibitors, but none are currently available. This study aimed to discover IL-6 inhibitors based on the PPI with a novel camelid Fab fragment, namely 68F2, in a crystal protein complex structure (PDB ID: 4ZS7). The pharmacophore models and molecular docking were used to screen compounds from DrugBank databases. The oral bioavailability of the top 24 ligands from the screening was predicted by the SwissAMDE tool. Subsequently, the selected molecules from docking and MD simulation illustrated a promising binding affinity in the formation of stable complexes at the active binding pocket of IL-6. Binding energies using the MM-PBSA technique were applied to the top 4 hit compounds. The result indicated that DB08402 and DB12903 could form strong interactions and build stable protein-ligand complexes with IL-6. These potential compounds may serve as a basis for further developing small molecule IL-6 inhibitors in the future.

Iridium(III) and Rhodium(III) Half-Sandwich Coordination Compounds with 11H-Indeno[1,2-b]quinoxalin-11-one Oxime: A Case of Spontaneous Resolution of Rh(III) Complex

Two half-sandwich iridium(III) and rhodium(III) complexes with 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) ligand were prepared by the reaction of the proligand with [M(Cp*)Cl2]2 (M = Ir, Rh) dimers. The reaction between IQ-1 and [Ir(Cp*)Cl2]2 in methanol gave the complex [Ir(Cp*)(IQ-1)Cl] (1), which crystallized in a centrosymmetric space group as a true racemate. Whereas complex [Rh(Cp*)(IQ-1)Cl] (2) in the form of a racemic conglomerate was obtained by the reaction of [Rh(Cp*)Cl2]2 and IQ-1 in methanol. The crystal structures of complexes 1 and 2 (R and S enantiomers) were determined by X-ray diffraction analysis, and the structural features were compared in order to understand the structural factors leading to the spontaneous enantiomer resolution of the rhodium(III) complex. In the crystal packing of 1, intermolecular C–H···C contacts between a pair of enantiomers link the molecules into centrosymmetric dimers and lead to the formation of heterochiral crystals of 1. In contrast, the intramolecular contacts CH···Cl and CH···C in complex 2 bind all three ligands around the chiral Rh(III) metal center. In addition, a combination of intermolecular CH···O and CH···C contacts leads to the formation of a homochiral supramolecular structure. These interactions altogether reinforce the spontaneous resolution in complex 2.

Synthesis, crystal structure, DFT and Hirshfeld surface analysis of Ni(II) complexes: Precursor for nickel sulfide nanoparticles

Homoleptic complexes, [Ni(iprbpedtc)2] (1) and [Ni(fbtfdtc)2](2) were prepared. Furthermore, 1 and 2 were used as synthon to prepare heteroleptic complexes, [Ni(iprbpedtc)(NCS)(PPh3)] (3) and [Ni(fbtfdtc)(NCS)(PPh3)](4) (where iprbpedtc is N-(4-isopropylbenzyl)-N-(2-phenylethyl)dithiocarbamate and fbtfdtc is N-(4-fluorobenzyl)-N-((tetrahydrofuran-2-yl)methyl)dithiocarbamate). The resulting complexes were characterized by elemental analysis, Fourier transform infrared, NMR (1H and 13C) and electronic spectroscopic techniques. The crystal structures of complexes 1, 3 and 4 were determined by single crystal X-ray diffraction and show that the dithiocarbamate ligands are coordinated to the nickel atom in the bidentate manner and the central atom is four coordinated. Hirshfeld surface analysis 1, 3 and 4 reveal that H…H interactions are the largest contribution in the molecular packing. In addition, the structures of 1, 3 and 4 were analyzed with DFT-based approaches. The analysis of the electrophilicity index indicates that complex 4 has the greater electrophilic character compared to those of 1 and 3. The catalytic activity of nanoparticles was evaluated for the degradation of rhodamine-6G dye. Complex 2 was used as a precursor for the preparation of nickel sulfide nanoparticles. Its morphology, structure and optical properties were evaluated using powder X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy and UV-Vis diffuse reflectance spectroscopy. PXRD study shows that the as-prepared nanoparticles consist of β-NiS and α-Ni22.52S19.44. EDS analysis confirms the formation nickel sulfide.

Binding of ion pairs and neutral guests by aryl-extended meso‑p-hydroxyphenyl calix[4]pyrrole: The interplay between three binding sites

An aryl-extended calix[4]pyrrole with four meso‑p-hydroxyphenyl substituents was investigated as a host for chloride, acetate, and benzoate anions. Crystal structures of pyridinium and imidazolium chloride complexes were obtained in which chloride ions are hydrogen bonded exo-cavity to the upper rim hydroxyl groups, and the aromatic cations are bound to the shallow cavity of the host. Furthermore, the calix[4]pyrrole formed a hydrogen bonded dimeric capsule templated by inclusion of adiponitrile guest in the endo-cavity binding site. NMR titrations revealed the preference of the OH groups of the host to bind anionic guests in solution. Benzoate anion had the highest binding constant (4 700 M−1) in acetonitrile. Density functional theory (DFT) calculations indicated that the exo-cavity complex with chloride anions was favoured by 23.2 kJ/mol over the endo-cavity complex, whereas the energies of endo- and exo-cavity benzoate complexes were of similar magnitude due to dispersion interactions between the host and the guest.

(Invited, Digital Presentation) Materials Aspects of New Ferroelectrics with Simple Crystal Structure

Ferroelectric materials are defined as the materials, of which spontaneous polarization can be switched by an external electric field. Their crystal structural symmetry makes them exhibit a variety of electric properties, such as piezoelectricity, pyroelectricity, and ferroelectricity. Because of their characteristics, they are expected to be adapted for various applications, including sensors, actuators, and non-volatile memories. Over the past decades, perovskite type ferroelectric materials have occupied the central position in both fundamental studies and applications of ferroelectric materials. On the other hand, there are a few studies on ferroelectrics with other crystal structures.This regime is now changing since HfO2-based new ferroelectric materials have been discovered. The HfO2-based dielectric materials are employed as high-k insulators of the metal-oxide-semiconductor field-effect-transistors instead of the conventional SiOx gate dielectrics, suggesting the high compatibility with semiconductor technologies. Thus, discovering ferroelectricity in HfO2-based materials strongly encourages us to develop highly integrated ferroelectric devices that are difficult to fabricate with traditional perovskite-type ferroelectrics. Amid increasing interest in ferroelectric materials, ferroelectricity is demonstrated on another new (Al, Sc)N, which has a wurtzite structure. Both fluorite structure, the parent structure of HfO2-based ferroelectrics, and wurtzite structure are simple compounds, having only a single anion and cation sites in the crystal structure. This feature contrasts the complex crystal structure of conventional perovskite structure. This presentation will give a brief outline of these new ferroelectric materials and introduce our recent studies from the viewpoint of crystal chemistry. It is well-known that HfO2 undergoes successive phase transitions from monoclinic to tetragonal and tetragonal to cubic phases. However, these phases cannot show ferroelectricity because of their inversion center in the crystal structure. It is widely accepted that the ferroelectricity in HfO2-based materials originates from the metastable orthorhombic structure. This orthorhombic structure was confirmed by the convergence electron diffraction and scanning transmission electron microscopy. Among the HfO2-based materials, HfO2- ZrO2 materials are most extensively studied. However, the thickness that can exhibit ferroelectricity in these materials is limited to less than 50 nm because of their strong preference for the monoclinic structure. In order to investigate structural features of the HfO2-based materials, materials are demanded that have ferroelectricity over the wide thickness range. The Y-doped HfO2 meets the requirement, allowing us to grow the ferroelectric film over 1 μm in thickness. Furthermore, we demonstrated ferroelectricity in epitaxial films using this composition. A recent report on ferroelectricity in bulk single-crystal also employed the Y-doped HfO2 system. The ferroelectricity in the wurtzite structure has been discussed for a long time. Moriwake et al. put forward giant spontaneous polarization in wurtzite materials by calculation based on density functional theory. The proposed mechanism of polarization reversal is accompanied by the change in the outermost surface, namely a cation surface to an anion surface and vice versa. Such large polarization was demonstrated in (Al1-x Scx)N films by Fitchtner et al. They also confirmed the change in the surface by performing chemical etching. In addition to (Al1-x Scx)N films, the ferroelectricity has been confirmed in (Al1-x B x )N, (Ga1-x Sc x )N, and (Zn1-x Mg x )O. For the wurtzite structure, we can consider the virtual paraelectric BN phase, in which both anions and cations are located in the same plane. As the paraelectric phase is deemed an intermediate state during polarization reversal, easy polarization reversal is expected as the u-parameter of the wurtzite structure approaches 0.5. It is considered that the u parameter is closely related to the axial ratio of the c- and a-axes. In fact, the reduction of coercive field and remanent polarization is ascertained experimentally. The “simple compound” ferroelectrics have attracted much attention due to their unique features, e.g., outstanding compatibility to semiconductor technologies in HfO2-based materials and giant remanent polarization in wurtzite materials. However, quite a large coercive field compared to conventional ferroelectrics reduces the reliability of the devices, particularly endurance properties. Further studies and developments to unveil microstructures under and after applying a strong electric field will lead to the next application of these ferroelectrics.

Discovery, evaluation and mechanism study of WDR5-targeted small molecular inhibitors for neuroblastoma.

Neuroblastoma is the most common and deadliest tumor in infancy. WDR5 (WD Repeat Domain 5), a critical factor supporting an N-myc transcriptional complex via its WBM site and interacting with chromosome via its WIN site, promotes the progression of neuroblastoma, thus making it a potential anti-neuroblastoma drug target. So far, a few WIN site inhibitors have been reported, and the WBM site disruptors are rare to see. In this study we conducted virtual screening to identify candidate hit compounds targeting the WBM site of WDR5. As a result, 60 compounds were selected as candidate WBM site inhibitors. Cell proliferation assay demonstrated 6 structurally distinct WBM site inhibitors, numbering as compounds 4, 7, 11, 13, 19 and 22, which potently suppressed 3 neuroblastoma cell lines (MYCN-amplified IMR32 and LAN5 cell lines, and MYCN-unamplified SK-N-AS cell line). Among them, compound 19 suppressed the proliferation of IMR32 and LAN5 cells with EC50 values of 12.34 and 14.89 μM, respectively, and exerted a moderate inhibition on SK-N-AS cells, without affecting HEK293T cells at 20 μM. Analysis of high-resolution crystal complex structure of compound 19 against WDR5 revealed that it competitively occupied the hydrophobic pocket where V264 was located, which might disrupt the interaction of MYC with WDR5 and further MYC-medicated gene transcription. By performing RNA-seq analysis we demonstrated the differences in molecular action mechanisms of the compound 19 and a WIN site inhibitor OICR-9429. Most interestingly, we established the particularly high synergy rate by combining WBM site inhibitor 19 and the WIN site inhibitor OICR-9429, providing a novel therapeutic avenue for neuroblastoma.

Structural and spectral studies on indium(III) complexes with 2,6-diacetylpyridine bis(benzoylhydrazones)

Complexes [In(L1)Cl(H2O)] (1), [In(L2)Cl(H2O)] (2) and [In(L3)Cl(H2O)] (3) were obtained with 2,6-diacetylpyridine bis(benzoylhydrazone) (H2L1) and its 2,6-diacetylpyridine bis(para-chlorobenzoylhydrazone) (H2L2) and 2,6-diacetylpyridine bis(para-methylbenzoylhydrazone) (H2L3) derivatives. The crystal structures of complexes (1) and (2) were determined, revealing a pentagonal bipyramidal arrangement around the indium(III) center. The spectral properties of complexes (1–3) were investigated. The complexes show fluorescence in DMSO solution resulting from increased conjugation and rigidity of the ligand, and a significant fluorescence brightness due to the strong light absorption in the near UV region. From the fluorescence spectra of 1–3 quantum yields in the 0.5 – 0.7 % range were determined using quinine hemisulfate monohydrate in H2SO4 0.5 M (ΦF = 0.546) as standard.

MHC2AffyPred: A machine-learning approach to estimate affinity of MHC class II peptides based on structural interaction fingerprints.

Understanding how MHC class II (MHC-II) binding peptides with differing lengths exhibit specific interaction at the core and extended sites within the large MHC-II pocket is a very important aspect of immunological research for designing peptides. Certain efforts were made to generate peptide conformations amenable for MHC-II binding and calculate the binding energy of such complex formation but not directed toward developing a relationship between the peptide conformation in MHC-II structures and the binding affinity (BA) (IC50 ). We present here a machine-learning approach to calculate the BA of the peptides within the MHC-II pocket for HLA-DRA1, HLA-DRB1, HLA-DP, and HLA-DQ allotypes. Instead of generating ensembles of peptide conformations conventionally, the biased mode of conformations was created by considering the peptides in the crystal structures of pMHC-II complexes as the templates, followed by site-directed peptide docking. The structural interaction fingerprints generated from such docked pMHC-II structures along with the Moran autocorrelation descriptors were trained using a random forest regressor specific to each MHC-II peptide lengths (9-19). The entire workflow is automated using Linux shell and Perl scripts to promote the utilization of MHC2AffyPred program to any characterized MHC-II allotypes and is made for free access at https://github.com/SiddhiJani/MHC2AffyPred. The MHC2AffyPred attained better performance (correlation coefficient [CC] of .612-.898) than MHCII3D (.03-.594) and NetMHCIIpan-3.2 (.289-.692) programs in the HLA-DRA1, HLA-DRB1 types. Similarly, the MHC2AffyPred program achieved CC between .91 and .98 for HLA-DP and HLA-DQ peptides (13-mer to 17-mer). Further, a case study on MHC-II binding 15-mer peptides of severe acute respiratory syndrome coronavirus-2 showed very close competency in computing the IC50 values compared to the sequence-based NetMHCIIpan v3.2 and v4.0 programs with a correlation of .998 and .570, respectively.