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Discovery of an anticancer medicine using a single target protein has often been unsuccessful due to the complexity of pathogenic mechanisms as well as the presence of redundant signaling pathways. In this work, we attempted to find promising anticancer drug candidates by simultaneously targeting casein kinase 1 delta (CK1δ) and muscarinic acetylcholine receptor M3 (M3R). Through the structure-based virtual screening and de novo design with the modified potential function for protein-ligand binding, a series of benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2-amine (BITA) derivatives were identified as CK1δ inhibitors and also as M3R antagonists. The biochemical potencies of these bifunctional molecules reached the nanomolar and low-micromolar levels with respect to CK1δ and M3R, respectively. A common interaction feature in the calculated CK1δ-inhibitor and M3R-antagonist complexes is that the BITA moiety is well-stabilized in the orthosteric site of M3R and the hinge region of CK1δ through the establishment of the three hydrogen bonds and the hydrophobic contacts in the vicinity. The computational and experimental results found in this work exemplify the efficiency of kinase and GPCR polypharmacology in developing anticancer medicines.Antimonene nanotubes, a class of important derivatives of the 2D counterpart (Sb monolayer), with transition metal (TM) atom adsorption were investigated systematically based on the first-principles calculations. For a stable geometry, the lengths of TM-Sb bonds on the tube surface strongly depend on their relative electronegativity. In particular, we find that the intrinsic magnetic moment magnitude of the TM atom plays a decisive role in inducing tube magnetism, and only TM atoms with a larger intrinsic magnetic moment (≥3.0 μB) can induce the magnetism for tubes. read more The strong interaction and coupling between the TM d-orbital and Sb p-orbital lead to variously favorable magnetic phases, such as the spin bipolar semiconductor and half-semiconductor, which is predicted to be stable beyond room temperature. In addition, the weakening or quenching of the magnetism for the adsorbed TM atom is intimately related to the expansion of the TM atom valence electron configuration and the charge transfer. Furthermore, the TM adsorption can also effectively regulate the tube carrier mobility to the difference of several orders of magnitude, and results in significant carrier polarity and spin polarity of mobility. A sensitive electric-magnetic coupling effect was also shown to cause continuous magnetic phase transition, providing more opportunity for obtaining magneto-electric materials.The "specific" interaction between metal cations (Na+, Ca2+, Mg2+, and Zn2+) and the charged COO- group, and the "non-specific" interaction between these cations and the peptide backbone of a zwitterionic trialanine (Ala3) in aqueous solutions were examined in detail, using linear infrared (IR) absorptions of the COO- symmetric stretching and the amide-II (mainly the C-N stretching) modes as IR probes. Different IR spectral changes in peak positions and intensities of the two IR probes clearly demonstrate their sensitivities to nearby cation distributions in distance and population. Quantum chemistry calculations and molecular dynamics simulations were used to describe the cation-peptide interaction picture. These combined results suggest that Na+ and Ca2+ tend to bind to the COO- group in the bidentate form, while Mg2+ and Zn2+ tend to bind to the COO- group in the pseudo-bridging form. The results also show that while all three divalent cations indirectly interact with the peptide backbone with large population, Ca2+ and Mg2+ can be sometimes distributed very close to the backbone. Such a non-specific cation interaction can be moderately sensed by the C-N stretching of the amide-II mode when cations approach the polar amide C[double bond, length as m-dash]O group, and is also influenced by the NH3+ charge group located at the N-terminus. The results suggest that the experimentally observed complication of the Hofmeister cation series shall be understood as a combined specific and non-specific cation-peptide interactions.Glucagon-like peptide-1 (GLP-1) signaling is an established therapeutic target for type 2 diabetes mellitus (T2DM). We developed a 7-step synthesis of N55, a positive modulator of GLP-1 signaling isolated from fenugreek (Trigonella foenum-graecum) seeds, with 29% overall yield, and we determined the absolute structure of N55 to be N-((3R,4R,5S)-4,5-dimethyl-2-oxotetrahydrofur-3-yl)linoleic amide.An efficient Cu and Mn co-mediated aerobic oxidative cyclization and azidation reaction of 1,3-enynes with amines and trimethylsilyl azide (TMSN3) for the synthesis of fully substituted azido pyrroles has been developed. The three-component reaction has the characteristics of high regioselectivity, wide substrate scope, and mild reaction conditions. A preliminary mechanism for this transformation is proposed.Eight new geranylquinol derivatives (1-8) were purified from the roots of Arnebia euchroma. Compounds 1-6 possess an unprecedented dearomatic benzocogeijerene skeleton with a rare trans-fused hydronaphthalene moiety. Their structures and absolute configurations were elucidated by HRESIMS, NMR, ECD, and X-ray diffraction. A convenient strategy for rapid determination of the relative configuration of H-1/H-7/Me-16 and the absolute configuration at C-1 for 1-6 was summarized. Compound 2 exhibited cytotoxicity against all the tested cell lines, namely PC9, BGC823, HCT116, HepG2, HeLa, and U87-MG, with IC50 values ranging from 13.7 to 29.3 μM.Source-gated transistors (SGTs) with Schottky barriers have emerged as extraordinary candidates for constructing low-power electronics by virtue of device simplicity, high gain, and low operation voltages. In this work, we demonstrate flexible low-power SGTs with solution processed In2O3 channels and Al2O3 gate dielectrics on ultrathin polymer substrates, exhibiting light area density (0.56 mg cm-2), low subthreshold swing (102 mV dec-1), low operation voltage ( less then 2 V), fast saturation behaviors (0.2 V), and low power consumption (46.3 μW cm-2). These achievements pave the way for employing the unconventional SGTs in wearable applications where low-power dissipation and high mechanical flexibility are essential.
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