Stafia-1: a STAT5a-Selective Inhibitor Developed via Docking-Based Screening of in Silico O-Phosphorylated Fragments

We present a new approach for the identification of inhibitors of phosphorylation-dependent protein–protein interaction domains, in which phenolic fragments are adapted by in silico O-phosphorylation before docking-based screening. From a database of 10 369 180 compounds, we identified 85 021 natural product-derived phenolic fragments, which were virtually O-phosphorylated and screened for in silico binding to the STAT3 SH2 domain. Nine screening hits were then synthesized, eight of which showed a degree of in vitro inhibition of STAT3. After analysis of its selectivity profile, the most potent inhibitor was then developed to Stafia-1, the first small molecule shown to preferentially inhibit the STAT family member STAT5a over the close homologue STAT5b. A phosphonate prodrug based on Stafia-1 inhibited STAT5a with selectivity over STAT5b in human leukemia cells, providing the first demonstration of selective in vitro and intracellular inhibition of STAT5a by a small-molecule inhibitor.     

SH wave propagation in a piezoelectric/piezomagnetic plate with an imperfect magnetoelectroelastic interface

In this paper, we investigate the SH wave propagation in a layered piezoelectric (PE) and piezomagnetic (PM) plate with an imperfect magnetoelectroelastic interface. A linear magnetoelectroelastic spring model is used to describe the weakness of the imperfect interface. On the basis of this model, dispersion curves and mode shapes of the SH waves are computed. In particular, a PZT-5A/CoFe₂O₄ composite plate is considered in the numerical examples to calculate the dispersion curves and the mode shapes for different combinations of the magnetic, electrical and elastic spring constants. The effects of the layer thickness ratio and the electric-magnetic boundary conditions on the dispersion curves are discussed in details. Our results show that for a general weak bonding case, the high modes of the dispersion curves are not monotonous in the range of small wave numbers. With the layer thickness ratio increasing, the wave velocities of the SH waves increase. The electric boundary conditions mainly determine the dispersion curves of the SH waves in the case of a small layer thickness ratio, i.e. a large thickness of the PE layer. The present results have relevant applications in the nondestructive testing and evaluation of the layered PE/PM plate-like wave devices.     

CH/pi hydrogen bonds determine the selectivity of the Src homology 2 domain to tyrosine phosphotyrosyl peptides: an ab initio fragment molecular orbital study

The CH/pi hydrogen bond is a weak molecular force occurring between CH groups (soft acids) and pi-systems (soft bases), and has been recognized to be important in the interaction of proteins with their specific ligands. For instance, it is well known that Src homology-2 protein (SH2) recognizes its specific pTyr peptide in two key regions, pTyr-binding region and specificity-determining region, by the use of attractive molecular forces, including the CH/pi hydrogen bond. We hypothesized that the CH/pi hydrogen bond plays a key role in determining the selectivity of SH2 proteins, and studied this issue by the ab initio fragment molecular orbital (FMO) method. The FMO calculations were carried out, at the HF/6-31G* and MP2/6-31G* level, for SH2 domains of Src, Grb2, P85alpha(N), Syk, and SAP, in complex with corresponding pTyr peptides. CH/pi hydrogen bonds have in fact been found to be important in stabilizing the structure of the complexes. We conclude that the CH/pi hydrogen bond plays an indispensable role in the recognition of SH2 domains with their specific pTyr peptides, thus playing a vital role in the signal transduction system.     

The Transition State of Free Radical SH2′ Reaction of Allyl Chloride with Organomercurial Study by Inverse Secondary α‐Deuterium Kinetic Isotope Effect

The concerted mechanism of free radical S_H2′ reaction of 2‐substituted allyl chloride was suggested again by inverse secondary α‐deuterium isotope effect. The transition state of free radical S_H2′ reaction of allyl chlorides seems to be symmetrical and is not as early as that of a free radical addition reaction.     

折线型裂纹对SH波的动力响应

利用Fourier积分变换方法,得出了无限平面中用裂纹位错密度函数表示的单裂纹散射场．根据无穷积分的性质,把单裂纹的散射场分解为奇异部分和有界部分．利用单裂纹的散射场建立了折线裂纹在SH波作用下的Cauchy型奇异积分方程．根据折线裂纹散射场和所得的积分方程讨论了裂纹在折点处的奇性应力及折点处的奇性应力指数．利用所得的奇性应力定义了折点处的应力强度因子．对所得Cauchy型奇积分方程的数值求解,可得裂纹端点和折点处的动应力强度因子。     

Synthesis and Crystal Structure of N,N′-Bis-[3-chloro-5-S-(l-menthyloxy)-2(5H)-4-furanon-yl]-propane-1,3-diamine

The title compound,N,N′-bis-[3-chloro-5-S-(l-menthyloxy)-2(5H)-4-furanon-yl]-propane-1,3-diamine(C31H48Cl2N2O6,Mr = 615.61),has been synthesized and characterized by IR,1H NMR,MS,elemental analysis and single-crystal X-ray diffraction.The crystal crystallizes in the monoclinic system,space group C2 with a = 16.1091(4),b = 11.1880(3),c = 19.2854(5) ,β = 106.297(2)°,V = 3336.12(15) 3,Z = 4,Dc = 1.226 mg/m3,μ = 0.237 mm-1,F(000) = 1320,the final R = 0.0531 and wR = 0.0700 for 2760 observed reflections(I > 2σ(I)).X-ray analysis reveals that the title compound possesses four rings:two chiral five-membered furanone rings and two six-membered cyclohexane rings with chair conformation,containing eight chiral centers:C2(S),C3(R),C5(R),C10(S),C18(S),C21(R),C22(S) and C25(R).The structure is stabilized by N-H…O hydrogen bonding interaction.     

Theoretical study on the reaction mechanisms of CH2SH + NO reaction

The mechanisms for the CH₂SH + NO reaction were investigated on both of the singlet and triplet PES at the BMC-CCSD//B3LYP/6-311+G(d,p) level. The results indicate that the singlet PES is much lower than the triplet PES energetically; therefore, the reaction occurs on the singlet PES dominantly. The most favorable channel on the singlet PES takes place by a barrierless addition of N atom to CH₂SH radical to form HSCH₂NO. Subsequently, the rearrangement of the initial adduct HSCH₂NO (IM1) to form another intermediate IM3 via a four-center transition state, followed by the C–O bond fission in IM3 leading to the major product CH₂S + HNO. Due to high barriers, other product including HC(N)SH + HO, HON + CH₂S, and HNO + CHSH could be negligible. The direct abstraction channel was also determined to yield CH₂S + HON. With high barrier (33.3 kcal/mol), it is not competitive with the addition channel, in which all stationary points are lower than reactant energetically. While on the triplet PES, with the lowest barrier height (18.8 kcal/mol), the direct N-abstracted channel to form CH₂S + HNO is dominant. However, it is not competitive with the channels on the singlet PES. Our results are in good accordance with experimental conclusions that the reaction proceeds via addition mechanism.     

SHEAR-HORIZONTAL WAVES IN A ROTATED Y-CUT QUARTZ PLATE WITH AN ISOTROPIC ELASTIC LAYER OF FINITE THICKNESS

We study shear-horizontal (SH) waves in a rotated Y-cut quartz plate carrying an isotropic elastic layer of finite thickness.The three-dimensional theories of anisotropic elasticity and isotropic elast...     

甲硫醇在Co修饰MoS2团簇边缘位的脱硫机理研究

由于国家对石油产品中含硫量的严格控制,原油脱硫已成为石油化工生产中的一项紧迫任务.硫化钼作为高效加氢脱硫催化剂而被广泛研究.过渡金属Co掺杂提高了传统钼基硫化物加氢脱硫催化剂的催化活性,目前被广泛应用于原油催化脱硫.本文采用密度泛函理论,对Co修饰MoS₂三角形团簇边缘不饱和活性位（CUS）的形成及甲硫醇的催化脱硫过程进行了理论研究.结果表明,活性位形成过程中,氢气裂解的活性位为Mo原子和S原子,随后形成硫化氢并脱附.甲硫醇倾向于吸附在CUS的Top^Co位.通过电荷布居及前线轨道分析发现,Co的引入改变了表面原子电荷及CUS的LUMO轨道分布,并且Co表现出强吸电子能力,从而促进甲硫醇的吸附.CH₃SH最优脱硫路径为先后断裂S-H和C-S键形成甲烷实现脱硫,其中形成甲烷的基元步骤为整个脱硫反应的速率控制步骤,其能垒为1.51 eV.     

Propagation of SH‐wave in an initially stressed orthotropic medium sandwiched by a homogeneous and an inhomogeneous semi‐infinite media

The paper presents a study of propagation of shear wave (SH‐wave) in an orthotropic elastic medium under initial stress sandwiched by a homogeneous semi‐infinite medium and an inhomogeneous half‐space. The technique of separation of variables has been adopted to get the analytical solutions for the dispersion relation in a closed form. The propagation of SH‐waves is influenced by inhomogeneity parameters and initial stress parameter. Velocities of SH‐waves are calculated numerically for different cases. As a special case when the intermediate layer and half‐space are homogeneous, computed frequency equation coincides with general equation of Love wave. To study the effect of inhomogeneity parameters and initial stress parameter, we have plotted the velocity of SH‐wave in several figures and observed that the velocity of wave decreases with the increases of non‐dimensional wave number. It can be found that the phase velocity decreases with the increase of inhomogeneity parameters. We observed that the velocity of SH‐wave decreases with the increases of initial stress parameter in both homogeneous and inhomogeneous media. GUI has been developed by using MATLAB to generalize the effect of the parameters discussed. Copyright © 2014 John Wiley & Sons, Ltd.