TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.     

Performance comparison using the GUESS mixture to evaluate counter-current chromatography instruments

Comparing the performance of different counter-current chromatography (CCC) J-type centrifuges has and will always be difficult. This is due to the number of variables such as speed of rotation, swung radius, β-value, column bore, column length that can be chosen during the design of an instrument. This situation is further complicated by the implication that some of these variables are intrinsically linked, such that if one is changed another or others can also change. The chromatographer has no influence on these hardware parameters once the instrument designer has chosen them. However, the chromatographer wants a CCC column that retains the most liquid stationary phase in order to achieve the best separation of the components in a mixture. What matters most is column performance in terms of: sample loading per injection, speed of separation, purity of target and yield of target. The instrument that has the best performance in all these areas is called a “high-performance” CCC system. This paper demonstrates to the modern chromatographer that a “high-performance” CCC instrument has shorter, lower volume columns that are rotated faster to provide quicker separations, even with the same sample loading.     

A novel approach to modelling counter-current chromatography

Literature lists a number of counter-current chromatography (CCC) models that can predict the retention time and to a certain extent the peak width of a solute eluting from a CCC column. The approach described in this paper distinguishes itself from previous reports by relating all model parameters directly to column dimensions and experimental settings. Most importantly, this model can predict a chromatogram from scratch without resorting to traditional calibration using empirical values. The model validation with experimental results obtained across a range of CCC instruments demonstrated that the solute retention time, peak width, and peak resolution could be predicted within reasonable accuracy. Additionally, the effect of several process parameters, such as mobile phase flow rate, rotational speed of the column or β-value, showed that the model is robust and applicable to a wide range of CCC instruments. Overall, this model proved to be a useful tool for parameter estimation and, most significantly, separation optimisation.     

${[\ell_p]}_{e.r}$ Euler-Riesz Difference Sequence Spaces

Başar and Braha [1], introduced the sequence spaces $\breve{\ell}_\infty$, $\breve{c}$ and $\breve{c}_0$ of Euler-Cesáro bounded, convergent and null difference sequences and studied their some properties. Then, in [2], we introduced the sequence spaces ${[\ell_\infty]}_{e.r}, {[c]}_{e.r}$ and ${[c_0]}_{e.r}$ of Euler-Riesz bounded, convergent and null difference sequences by using the composition of the Euler mean $E_1$ and Riesz mean $R_q$ with backward difference operator $\Delta$. The main purpose of this study is to introduce the sequence space ${[\ell_p]}_{e.r}$ of Euler-Riesz $p-$absolutely convergent series, where $1 \leq p <\infty$, difference sequences by using the composition of the Euler mean $E_1$ and Riesz mean $R_q$ with backward difference operator $\Delta$. Furthermore, the inclusion $\ell_p\subset{[\ell_p]}_{e.r}$ hold, the basis of the sequence space ${[\ell_p]}_{e.r}$ is constructed and $\alpha-$, $\beta-$ and $\gamma-$duals of the space are determined. Finally, the classes of matrix transformations from the ${[\ell_p]}_{e.r}$ Euler-Riesz difference sequence space to the spaces $\ell_\infty, c$ and $c_0$ are characterized. We devote the final section of the paper to examine some geometric properties of the space ${[\ell_p]}_{e.r}$.     

Synthesis,characterization, fluorescence and redox features of new <Emphasis Type="Italic">vic</Emphasis>-dioxime ligand bearing pyrene and its metal complexes

A new vic-dioxime ligand, N,N′-bis(aminopyreneglyoxime) (LH₂), and its copper(II), nickel(II) and cobalt(II) metal complexes were synthesized and characterized by elemental analyses, IR, UVVIS and ¹H and ¹³C NMR spectra (for the ligand). Mononuclear complexes were synthesized by a reaction of ligand (LH₂) and salts of Co(II), Ni(II), and Cu(II) in ethanol. The complexes have the metal-ligand ratio of 1: 2 and metals are coordinated by N,N′ atoms of vicinal dioximes. The ligand acts in a polydentate fashion bending through nitrogen atoms in the presence of a base, as do most vic-dioximes. Detection of a H-bonding in the Co(II), Ni(II), and Cu(II) complexes by IR revealed the square-planar MN₄ coordination of mononuclear complexes. Fluorescent properties of the ligand and its complexes arise from pyrene units conjugated with a vic-dioxime moiety. Fluorescence emission spectra of the ligand showed a drastic decrease in its fluorescence intensity upon metal binding. The electrochemical properties of the complexes were studied by the cyclic voltammetry technique. The nickel complex displayed an irreversible oxidation process while the copper complex exhibited a quasi-reversible oxidation and reduction processes based on the copper Cu(II)/Cu(III) and Cu(II)/Cu(I) couples, respectively.     

Theoretical investigations on nonlinear optical and spectroscopic properties of 6-(3,3,4,4,4-pentafluoro-2-hydroxy-1-butenyl)-2,4-pyrimidinedione: An efficient NLO material

In this study, quantum chemical calculations of geometric parameters, conformational, natural bond orbital (NBO) and nonlinear optical (NLO) properties, vibrational frequencies, ¹H and ¹³C NMR chemical shifts of the title molecule [C₉H₇F₅N₂O₃] in the ground state have been calculated with the help of Density Functional Theory (DFT-B3LYP/6-311++G(d,p)) and Hartree-Fock (HF/6-311++G(d,p)) methods. The optimized geometric parameters, vibrational frequencies, ¹H and ¹³C NMR chemical shifts values are compared with experimental values of the investigated molecules. Comparison between experimental and theoretical results showed that B3LYP/6-311++G(d,p) method is able to provide more satisfactory results. In order to understand this phenomenon in the context of molecular orbital picture, we examined the molecular frontier orbital energies (HOMO, HOMO-1, LUMO, and LUMO + 1), the energy difference (ΔE) between E _HOMO and E _LUMO, electronegativity (χ), hardness (η), softness (S) calculated by HF/6-311++G(d,p) and B3LYP/6-311++G(d,p) levels. The molecular surfaces, Mulliken, NBO, and Atomic polar tensor (APT) charges of the investigated molecule have also been calculated by using the same methods.     

Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 methyltransferase activity

We described herein structure-based design,synthesis and evaluation of conformationally constrained,cyclic peptidomimetics to block the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 histone methyltransferase activity.Our study has yielded cyclic peptidomimetics with very high binding affinities to WDR5(Kivalues 1 nmol/L) and function as antagonists of the MLL1 histone methyltransferase activity.     

Investigation of irradiated 1H-Benzo[b]pyrrole by ESR,thermal methods and learning algorithm

1H-Benzo[b]pyrrole samples were irradiated in the air with gamma source at 0.969?kGy per hour at room temperature for 24, 48 and 72?h. After irradiation, electron spin resonance, thermogravimetry analysis (TGA) and differential thermal analysis (DTA) measurements were immediately carried out on the irradiated and unirradiated samples. The ESR measurements were performed between 320 and 400?K. ESR spectra were recorded from the samples irradiated for 48 and 72?h. The obtained spectra were observed to be dependent on temperature. Two radical-type centres were detected on the sample. Detected radiation-induced radicals were attributed to R-^+?NH and R=^?CC₂H₂. The g-values and hyperfine constants were calculated by means of the experimental spectra. It was also determined from TGA spectrum that both the unirradiated and irradiated samples were decomposed at one step with the rising temperature. Moreover, a theoretical study was presented. Success of the machine learning methods was tested. It was found that bagging techniques, which are widely used in the machine learning literature, could optimise prediction accuracy noticeably.