Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches

Targeting enzymes that play a role in the biosynthesis of the bacterial cell wall has long been a strategy for antibacterial discovery. In particular, the cell wall of Mycobacterium tuberculosis (Mtb) is a complex of three layers, one of which is Peptidoglycan, an essential component providing rigidity and strength. UDP-GlcNAc, a precursor for the synthesis of peptidoglycan, is formed by GlmU, a bi-functional enzyme. Inhibiting GlmU Uridyltransferase activity has been proven to be an effective anti-bacterial, but its similarity with human enzymes has been a deterrent to drug development. To develop Mtb selective hits, the Mtb GlmU substrate binding pocket was compared with structurally similar human enzymes to identify selectivity determining factors. Substrate binding pockets and conformational changes upon substrate binding were analyzed and MD simulations with substrates were performed to quantify crucial interactions to develop critical pharmacophore features. Thereafter, two strategies were applied to propose potent and selective bacterial GlmU Uridyltransferase domain inhibitors: (i) optimization of existing inhibitors, and (ii) identification by virtual screening. The binding modes of hits identified from virtual screening and ligand growing approaches were evaluated further for their ability to retain stable contacts within the pocket during 20 ns MD simulations. Hits that are predicted to be more potent than existing inhibitors and selective against human homologues could be of great interest for rejuvenating drug discovery efforts towards targeting the Mtb cell wall for antibacterial discovery.     

Multi-State Second-Order Nonlinear Optical Switches Incorporating One to Three Benzazolo-Oxazolidine Units: A Quantum Chemistry Investigation

This contribution employs quantum chemistry methods to describe the variations of the second nonlinear optical responses of molecular switches based on benzazolo-oxazolidine (BOX) units, connected by π-linkers, along their successive opening/closing. Under the fully closed forms, all of them display negligible first hyperpolarizability (β) values. When one BOX is opened, which is sketched as C→O, a push–pull π-conjugated segment is formed, having the potential to enhance β and to set the depolarization ratio (DR) to its one-dimensional-like value (DR = 5). This is observed when only one BOX is open, either for the monoBOX species (C→O) or for the diBOX (CC→CO) and triBOX (CCC→CCO) compounds, i.e., when the remaining BOXs stay closed. The next BOX openings have much different effects. For the diBOXs, the second opening (CO→OO) is associated with a decrease of β, and this decrease is tuned by controlling the conformation of the π-linker, i.e., the centrosymmetry of the whole compound because β vanishes in centrosymmetric compounds. For the triBOXs, the second opening gives rise to a Λ-shape compound, with a negligible change of β, but a decrease of the DR whereas, along the third opening, β remains similar and the DR decreases to the typical value of octupolar systems (DR = 1.5).     

Molecular Beam Epitaxy of Nonstoichiometric Semiconductors and Multiphase Material Systems

When arsenides are grown by molecular beam epitaxy at low substrate temperatures, as much as 2% excess arsenic can be incorporated into the epilayer. This excess arsenic is in the form of antisites, but there is also a substantial concentration of gallium vacancies. With anneal, there is a significant decrease in the arsenic antisite and gallium vancancy concentrations as the excess arsenic precipitates. With further anneal, the arsenic precipitates coarsen. This combination of low substrate temperature molecular beam epitaxy and a subsequent anneal results in a broad spectrum of materials, from highly defected epilayers to a two-phase system of semimetallic arsenic precipitates in an arsenide semiconductor matrix. These materials exhibit some very interesting and useful electrical and optical properties.     

Effect of H impurity on misfit dislocation in Ni-based single-crystal superalloy： molecular dynamic simulations

The effect of H impurity on the misfit dislocation in Ni-based single-crystal superalloy is investigated using the molecular dynamic simulation.It includes the site preferences of H impurity in single crystals Ni and Ni 3 Al,the interaction between H impurity and the misfit dislocation and the effect of H impurity on the moving misfit dislocation.The calculated energies and simulation results show that the misfit dislocation attracts H impurity which is located at the γ/γˊinterface and Ni₃ Al and H impurity on the glide plane can obstruct the glide of misfit dislocation,which is beneficial to improving the mechanical properties of Ni based superalloys.     

A relativistic density functional study of gaseous uranium tetrahalides

The molecular structures and vibrational frequencies of gaseous UX₄ (X = F, Cl, Br and I) molecules have been investigated using generalized gradient approximation (GGA) functions (BP, BLYP, PBE and RPBE) with triple-zeta polarized (TZP) basis set. Scalar relativistic effects are introduced via the zeroth-order regular approximation (ZORA) approach to the Dirac equation in the present study. Of the methods examined here the RPBE has the best performance in terms of the errors compared with experiment and reference for the vibrational frequencies. The bond dissociation energies (BDE) for U–X bonds in the UX₄ were obtained using the RPBE method, and are in good agreement with experimental values. In addition, satisfactory calculated entropies of UX₄ have also been obtained at temperatures ranging from 600 to 1200 K in 50 steps using the same method.     

Exploring the Parallel G-Quadruplex Nucleic Acid World: A Spectroscopic and Computational Investigation on the Binding of the c-myc Oncogene NHE III1 Region by the Phytochemical Polydatin

Trans-polydatin (tPD), the 3-β-D-glucoside of the well-known nutraceutical trans-resveratrol, is a natural polyphenol with documented anti-cancer, anti-inflammatory, cardioprotective, and immunoregulatory effects. Considering the anticancer activity of tPD, in this work, we aimed to explore the binding properties of this natural compound with the G-quadruplex (G4) structure formed by the Pu22 [d(TGAGGGTGGGTAGGGTGGGTAA)] DNA sequence by exploiting CD spectroscopy and molecular docking simulations. Pu22 is a mutated and shorter analog of the G4-forming sequence known as Pu27 located in the promoter of the c-myc oncogene, whose overexpression triggers the metabolic changes responsible for cancer cells transformation. The binding of tPD with the parallel Pu22 G4 was confirmed by CD spectroscopy, which showed significant changes in the CD spectrum of the DNA and a slight thermal stabilization of the G4 structure. To gain a deeper insight into the structural features of the tPD-Pu22 complex, we performed an in silico molecular docking study, which indicated that the interaction of tPD with Pu22 G4 may involve partial end-stacking to the terminal G-quartet and H-bonding interactions between the sugar moiety of the ligand and deoxynucleotides not included in the G-tetrads. Finally, we compared the experimental CD profiles of Pu22 G4 with the corresponding theoretical output obtained using DichroCalc, a web-based server normally used for the prediction of proteins’ CD spectra starting from their “.pdb” file. The results indicated a good agreement between the predicted and the experimental CD spectra in terms of the spectral bands’ profile even if with a slight bathochromic shift in the positive band, suggesting the utility of this predictive tool for G4 DNA CD investigations.     

微波放电解离氯分子解离效率的测量

以Cl/Cl2/HN3/He为基础的NCl(a1Δ)/I作为一种化学激光新的体系,氯原子产生的多少对该体系的研究是至关重要的。利用滴定法研究了微波解离氯分子的解离效率。用HN3/He滴定Cl,由光学多通道分析仪监测NCl(a1Δ)和NCl(b1Σ)辐射的荧光。发现微波解离氯分子的效率并不是想象的那样低,在较小的氯流量下,最高的解离效率可以达到100％。     

串联组装双C60 的电子结构和输运特性

利用第一原理密度泛函理论计算组装C60形成能和电子结构,用半经典隧穿理论研究了串联C60的电子输运特性。结果显示：六边形对六边形双C60比边对边双C60稳定;库仑阻塞与系统的结构密切相关,并且只有阴极结比阳极结窄时,才会出现库仑阻塞;低温时出现非常明显库仑台阶,温度较高时其被热效应抑制。     

Helium blistering of niobium: Large swelling measurements supporting the gas pressure model

Crystal potentials are usually obtained through a combination of theoretical calculation and the fitting of crystal properties. Because of thermal expansion of the crystal, the equilibrium condition is not satisfied at all temperatures unless the crystal potential is made temperature-dependent. A quasiharmonic potential that satisfies the equilibrium condition at all temperatures is derived from KC1 and used to calculate temperature-dependent defect energies (at constant volume). Other thermodynamic defect parameters are then derived by combining these results with the experimental Gibbs energies. The temperature-dependence of these parameters is displayed.     

Hcp-icosahedron structural transformation induced by the change in Ag concentration during the freezing of （CoAg）561 clusters

The synergy effect of alloy elements in bimetallic clusters can be used to tune the chemical and physical properties. Research on the influences of alloy concentration and distribution on the frozen structure of bimetallic clusters plays a key rolc in exploring new structural materials. In this paper, we study the influence of Ag concentration on the frozen structure of the （AgCo）561 cluster by using molecular dynamics simulation with a general embedded atom method. The results indicate that tt~e structure and chemical ordering of the （AgCo）561 cluster are strongly related to Ag concentration. Hcp-icosahedron structural transformation in the frozen （CoAg）561 cluster can be induced by changing Ag concentration. The chemical ordering also transforms to Janus-like Co Ag from core-shell Co-Ag.