The tau-tubulin kinase 1 (TTBK1) protein is a casein kinase 1 superfamily member located at chromosome 6p21.1. It is expressed explicitly in the brain, particularly in the cytoplasm of cortical and hippocampal neurons. TTBK1 has been implicated in the phosphorylation and aggregation of tau in Alzheimer\'s disease (AD). Considering its significance in AD, TTBK1 has emerged as a promising target for AD treatment. In the present study, we identified novel TTBK1 inhibitors using various computational techniques. We performed a virtual screening-based docking study followed by E-pharmacophore modeling, cavity-based pharmacophore, and ligand design techniques and found ZINC000095101333, LD7, LD55, and LD75 to be potential novel TTBK1 lead inhibitors. The docking results were complemented by Molecular Mechanics/Generalized Born Surface Area (MMGBSA) calculations. The molecular dynamics (MD) simulation studies at a 500 ns scale were carried out to monitor the behavior of the protein toward the identified ligands. Pharmacological and ADME/T studies were carried out to check the drug-likeness of the compounds. In summary, we identified a new series of compounds that could effectively bind the TTBK1 receptor. The newly designed compounds are promising candidates for developing therapeutics targeting TTBK1 for AD.

Trinuclear metallacyclic oxidovanadium(V) complexes, [{VO(L3+2R)}3] (1-3) with asymmetric multidentate linking ligands (H3L3+2R: R = H, Me, Br), were synthesized. The molecular structure of 1 is characterized as a tripod structure, with each V(V) ion coordinated by ONO-atoms from a tridentate Schiff base site and ON-atoms from a bidentate benzoxazole site of two respective H3L3+2H ligands. The intramolecular V⋯V distances range from 8.0683 to 8.1791 Å. Complex 4 is a mononuclear dioxidovanadium(V) complex, (Et3NH)[VO2(HL3+2H)]. Cyclic voltammograms of 1-3 in DMF revealed redox couples attributed to three single-electron transfer processes.

Perovskite nanocrystals (PNCs) bear a huge potential for widespread applications, such as color conversion, X-ray scintillators, and active laser media. However, the poor intrinsic stability and high susceptibility to environmental stimuli including moisture and oxygen have become bottlenecks of PNC materials for commercialization. Appropriate barrier material design can efficiently improve the stability of the PNCs. Particularly, the strategy for packaging PNCs in organosilicon matrixes can integrate the advantages of inorganic-oxide-based and polymer-based encapsulation routes. However, the inert long-carbon-chain ligands (e.g., oleic acid, oleylamine) used in the current ligand systems for silicon-based encapsulation are detrimental to the cross-linking of the organosilicon matrix, resulting in performance deficiencies in the nanocrystal films, such as low transparency and large surface roughness. Herein, we propose a dual-organosilicon ligand system consisting of (3-aminopropyl)triethoxysilane (APTES) and (3-aminopropyl)triethoxysilane with pentanedioic anhydride (APTES-PA), to replace the inert long-carbon-chain ligands for improving the performance of organosilicon-coated PNC films. As a result, strongly fluorescent PNC films prepared by a facile solution-casting method demonstrate high transparency and reduced surface roughness while maintaining high stability in various harsh environments. The optimized PNC films were eventually applied in an X-ray imaging system as scintillators, showing a high spatial resolution above 20 lp/mm. By designing this promising dual organosilicon ligand system for PNC films, our work highlights the crucial influence of the molecular structure of the capping ligands on the optical performance of the PNC film.

We disclose the development of a Cu-catalyzed C-O coupling method utilizing a new N1,N2-diarylbenzene-1,2-diamine ligand, L8. Under optimized reaction conditions, structurally diverse aryl and heteroaryl bromides underwent efficient coupling with a variety of alcohols at room temperature using an L8-based catalyst. Notably, the L8-derived catalyst exhibited enhanced activity when compared to the L4-based system previously disclosed for C-N coupling, namely the ability to functionalize aryl bromides containing acidic functional groups. Mechanistic studies demonstrate that C-O coupling utilizing L8 ⋅ Cu involves rate-limiting alkoxide transmetallation, resulting in a mechanism of C-O bond formation that is distinct from previously described Pd-, Cu-, or Ni-based systems. This lower energy pathway leads to rapid C-O bond formation; a 7-fold increase relative to what is seen with other ligands. The results presented in this report overcome limitations in previously described C-O coupling methods and introduce a new ligand that we anticipate may be useful in other Cu-catalyzed C-heteroatom bond-forming reactions.

IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and IPr (IPr=1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represent by far the most frequently used N-heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N-heterocyclic carbene ligands that are characterized by freely-rotatable N-aromatic wingtips in the imidazol-2-ylidene architecture. The combination of rotatable N-CH2 Ar bond with conformationally-fixed N-Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)-catalyzed β-hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron-containing compounds. The most reactive Cu(I)-NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vbur geometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vbur described for an IPr analogue, while retaining full flexibility of N-wingtip. Considering the modular access to novel geometrical space in N-heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.

The outbreak of coronavirus disease 2019 (COVID-19) has sparked an urgent demand for advanced diagnosis and vaccination worldwide. The discovery of high-affinity ligands is of great significance for vaccine and diagnostic reagent manufacturing. Targeting the receptor binding domain (RBD) from the spike protein of severe acute respiratory syndrome-coronavirus 2, an interface at the outer surface of helices on the Z domain from protein A was introduced to construct a virtual library for the screening of ZRBD affibody ligands. Molecular docking was performed using HADDOCK software, and three potential ZRBD affibodies, ZRBD-02, ZRBD-04, and ZRBD-07, were obtained. Molecular dynamics (MD) simulation verified that the binding of ZRBD affibodies to RBD was driven by electrostatic interactions. Per-residue free energy decomposition analysis further substantiated that four residues with negative-charge characteristics on helix α1 of the Z domain participated in this process. Binding affinity analysis by microscale thermophoresis showed that ZRBD affibodies had high affinity for RBD binding, and the lowest dissociation constant was 36.3 nmol/L for ZRBD-07 among the three potential ZRBD affibodies. Herein, ZRBD-02 and ZRBD-07 affibodies were selected for chromatographic verifications after being coupled to thiol-activated Sepharose 6 Fast Flow (SepFF) gel. Chromatographic experiments showed that RBD could bind on both ZRBD SepFF gels and was eluted by 0.1 mol/L NaOH. Moreover, the ZRBD-07 SepFF gel had a higher affinity for RBD. This research provided a new idea for the design of affibody ligands and validated the potential of affibody ligands in the application of RBD purification from complex feedstock.

暂无摘要。

Incorporating design elements from homogeneous catalysts to construct well defined active sites on electrode surfaces is a promising approach for developing next generation electrocatalysts for energy conversion reactions. Furthermore, if functionalities that control the electrode microenvironment could be integrated into these active sites it would be particularly appealing. In this context, a square planar nickel calixpyrrole complex, Ni(DPMDA) (DPMDA=2,2\'-((diphenylmethylene)bis(1H-pyrrole-5,2-diyl))bis(methaneylylidene))bis(azaneylylidene))dianiline) with pendant amine groups is reported that forms a heterogeneous hydrogen evolution catalyst using anilinium tetrafluoroborate as the proton source. The supported Ni(DPMDA) catalyst was surprisingly stable and displayed fast reaction kinetics with turnover frequencies (TOF) up to 25,900 s-1 or 366,000 s-1  cm-2 . Kinetic isotope effect (KIE) studies revealed a KIE of 5.7, and this data, combined with Tafel slope analysis, suggested that a proton-coupled electron transfer (PCET) process involving the pendant amine groups was rate-limiting. While evidence of an outer-sphere reduction of the Ni(DPMDA) catalyst was observed, it is hypothesized that the control over the secondary coordination sphere provided by the pendant amines facilitated such high TOFs and enabled the PCET mechanism. The results reported herein provide insight into heterogeneous catalyst design and approaches for controlling the secondary coordination sphere on electrode surfaces.

Amphotericin B has been an essential drug in the fight against leishmaniasis and fungal pathogens for decades, and has more recently gained attention for the very limited microbial resistance displayed against it. However, its toxicity has restricted its use to only the most severe cases of disease, and attempts to reduce these ill effects via formulation have had only minor success. Genetic engineering has allowed the development of superior amphotericin analogues, notably 16-descarboxyl-16-methyl amphotericin B (MeAmB), which shows a ten-fold reduction in toxicity in addition to a slight improvement in therapeutic activity. However, MeAmB is difficult to extract from its bacterial source and purify. Presented here is an alternative method of MeAmB purification. A biomimetic polymer with a high affinity for MeAmB was designed via computational modelling and synthesised. Prepared as a separation column, the polymer was able to retain the target MeAmB whilst allowing the removal of cell debris from the bacterial extract. Starting with a simple bacterial extract, the relatively simple process allowed the purification of an MeAmB salt complex at approximately 70% MeAmB, and likely higher purification from further extraction. The mean MeAmB recovery between the pre-purification extract sample and the final product was 81%. This is the first successful demonstration of extraction or purification of any amphotericin molecule with any polymeric material. The biomimetic polymer was additionally reusable and simple to fabricate, giving this technique significant advantages over traditional methods of extraction and purification of valuable compounds.

Polydentate ligands are used for thermodynamic stabilization of tetrylenes-low-valent derivatives of Group 14 elements (E = Si, Ge, Sn, Pb). This work shows by DFT calculations how the structure (the presence or absence of substituents) and type (alcoholic, Alk, or phenolic, Ar) of tridentate ligands 2,6-pyridinobis(1,2-ethanols) [AlkONOR]H2 and 2,6-pyridinobis(1,2-phenols) [ArONOR]H2 (R = H, Me) may affect the reactivity or stabilization of tetrylene, indicating the unprecedented behavior of Main Group elements. This enables the unique control of the type of the occurring reaction. We found that unhindered [ONOH]H2 ligands predominantly led to hypercoordinated bis-liganded {[ONOH]}2Ge complexes, where an E(+2) intermediate was inserted into the ArO-H bond with subsequent H2 evolution. In contrast, substituted [ONOMe]H2 ligands gave [ONOMe]Ge: germylenes, which may be regarded as kinetic stabilized products; their transformation into E(+4) species is also thermodynamically favorable. The latter reaction is more probable for phenolic [ArONO]H2 ligands than for alcoholic [AlkONO]H2. The thermodynamics and possible intermediates of the reactions were also investigated.