Synthesis and optimization of peptidomimetics as HIV entry inhibitors against the receptor protein CD4 using STD NMR and ligand docking

We recently described the design and synthesis of a novel CD4 binding peptidomimetic as a potential HIV entry inhibitor with a KD value of approximately 35 microM and a high proteolytic stability [A. T. Neffe and B. Meyer, Angew. Chem., Int. Ed., 2004, 43, 2937-2940]. Based on saturation transfer difference (STD) NMR analyses and docking studies of peptidomimetics we now report the rational design, synthesis, and binding properties of 11 compounds with improved binding affinity. Surface plasmon resonance (SPR) resulted in a KD = 10 microM for the best peptidomimetic XI, whose binding affinity is confirmed by STD NMR (KD = 9 microM). The STD NMR determined binding epitope of the ligand indicates a very similar binding mode as that of the lead structure. The binding studies provide structure activity relationships and demonstrate the utility of this approach.     

Computational study of the structure and behavior of aqueous mixed system sodium unsaturated carboxylate-dodecyltrimethylammonium bromide

The mixed surfactant system sodium 10-undecenoate (SUD)-dodecyltrimethylammonium bromide (DTAB) was studied by computational simulation to determine the composition and structure of the mixed microstructures. Results were contrasted with experimental data obtained from literature and our own laboratory. The modelization predicts spherical or cylindrical micelles with a preferential composition of SUD-DTAB of about 1:2, while the system predicts a lamellar structure with a proportion of 1:1 when SUD is replaced by the saturated soap sodium undecanoate. The model also predicts the deep inclusion of bromide ions in the micelle Stern layer. All predictions were in agreement with previous experimental results.     

New ligands for a general palladium-catalyzed amination of aryl and heteroaryl chlorides

The synthesis and application of monodentate N-substituted heteroarylphosphines is described. In general, the ligands are conveniently prepared by selective metallation at the 2-position of the respective N-substituted heterocycle (pyrrole, indole) by using n-butyllithium/tetramethylethylenediamine (TMEDA) followed by quenching with dialkyl- or diarylchlorophosphines. Of the different ligands prepared, the new dialkyl-2-(N-arylindolyl)phosphines (cataCXium P) perform excellently in the palladium-catalyzed amination of aryl and heteroaryl chlorides. Coupling of both activated and deactivated chloroarenes proceeds under mild conditions (room temperature to 60 degrees C). By using optimized conditions remarkable catalyst productivity (total turnover number, TON, up to 8000) and activity (turnover frequency, TOF=14000 h(-1) at 75% conversion) are observed.     

Radical Cations and Radical Anions of Three Bridgehead Azopolycycloalkanes: A fluid-solution ESR study

The radical mono-ions of three azoalkanes in which the azo group is connected to the polycyclic alkane moieties at the bridgehead C-atoms, i.e. 1,1′-azonorbornane ( 1 ), 1,1′-azotwistane ( 2 ), and 1,1′-azobicyclo[3.2.1]octane ( 3 ), were studied in fluid solution by ESR spectroscopy. According to the ESR parameters and MO models, the radical cations of 1–3 should be considered as σ radicals, whereas the corresponding radical anions are π radicals. INDO calculations point to a a remarkable dependence of the ¹⁴N-coupling constants on the geometry at the N-atoms in the radical cations of aliphatic azo compounds.     

Triplet Emitting C^N^C Cyclometalated Dibenzo[c,h]Acridine Pt(II) Complexes

In a series of Pt(II) complexes [Pt(dba)(L)] containing the very rigid, dianionic, bis-cyclometalating, tridentate C^N^C²⁻ heterocyclic ligand dba^2– (H₂dba = dibenzo[c,h]acridine), the coligand (ancillary ligand) L = dmso, PPh₃, CNtBu and Me₂Imd (N,N’-dimethylimidazolydene) was varied in order to improve its luminescence properties. Beginning with the previously reported dmso complex, we synthesized the PPh₃, CNtBu and Me₂Imd derivatives and characterized them by elemental analysis, ¹H (and ³¹P) NMR spectroscopy and MS. Cyclic voltammetry showed partially reversible reduction waves ranging between −1.89 and −2.10 V and increasing along the series Me₂Imd < dmso ≈ PPh₃ < CNtBu. With irreversible oxidation waves ranging between 0.55 (L = Me₂Imd) and 1.00 V (dmso), the electrochemical gaps range between 2.65 and 2.91 eV while increasing along the series Me₂Imd < CNtBu < PPh₃ < dmso. All four complexes show in part vibrationally structured long-wavelength absorption bands peaking at around 530 nm. TD-DFT calculated spectra agree quite well with the experimental spectra, with only a slight redshift. The photoluminescence spectra of all four compounds are very similar. In fluid solution at 298 K, they show broad, only partially structured bands, with maxima at around 590 nm, while in frozen glassy matrices at 77 K, slightly blue-shifted (~580 nm) bands with clear vibronic progressions were found. The photoluminescence quantum yields Φ_L ranged between 0.04 and 0.24, at 298 K, and between 0.80 and 0.90 at 77 K. The lifetimes τ at 298 K ranged between 60 and 14040 ns in Ar-purged solutions and increased from 17 to 43 µs at 77 K. The TD-DFT calculated emission spectra are in excellent agreement with the experimental findings. In terms of high Φ_L and long τ, the dmso and PPh₃ complexes outperform the CNtBu and Me₂Imd derivatives. This is remarkable in view of the higher ligand strength of Me₂Imd, compared with all other coligands, as concluded from the electrochemical data.     

Decreased Water Mobility Contributes To Increased α-Synuclein Aggregation**

The solvation shell is essential for the folding and function of proteins, but how it contributes to protein misfolding and aggregation has still to be elucidated. We show that the mobility of solvation shell H₂O molecules influences the aggregation rate of the amyloid protein α-synuclein (αSyn), a protein associated with Parkinson's disease. When the mobility of H₂O within the solvation shell is reduced by the presence of NaCl, αSyn aggregation rate increases. Conversely, in the presence CsI the mobility of the solvation shell is increased and αSyn aggregation is reduced. Changing the solvent from H₂O to D₂O leads to increased aggregation rates, indicating a solvent driven effect. We show the increased aggregation rate is not directly due to a change in the structural conformations of αSyn, it is also influenced by a reduction in both the H₂O mobility and αSyn mobility. We propose that reduced mobility of αSyn contributes to increased aggregation by promoting intermolecular interactions.     

DMEA: a direction-based multiobjective evolutionary algorithm

A novel direction-based multi-objective evolutionary algorithm (DMEA) is proposed, in which a population evolves over time along some directions of improvement. We distinguish two types of direction: (1) the convergence direction between a non-dominated solution (stored in an archive) and a dominated solution from the current population; and, (2) the spread direction between two non-dominated solutions in the archive. At each generation, these directions are used to perturb the current parental population from which offspring are produced. The combined population of offspring and archived solutions forms the basis for the creation of both the next-generation archive and parental pools. The rule governing the formation of the next-generation parental pool is as follows: the first half is populated by non-dominated solutions whose spread is aided by a niching criterion applied in the decision space. The second half is filled with both non-dominated and dominated solutions from the sorted remainder of the combined population. The selection of non-dominated solutions for the next-generation archive is also assisted by a mechanism, in which neighborhoods of rays in objective space serve as niches. These rays originate from the current estimate of the Pareto optimal front??s (POF??s) ideal point and emit randomly into the hyperquadrant that contains the current POF estimate. Experiments on two well-known benchmark sets, namely ZDT and DTLZ have been carried out to investigate the performance and the behavior of the DMEA. We validated its performance by comparing it with four well-known existing algorithms. With respect to convergence and spread performance, DMEA turns out to be very competitive.