Receptor-based computational screening of compound databases: the main docking-scoring engines

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance with many new and exciting techniques. The number of protein structures and/or chemical ligands is constantly growing, through the use of parallel chemistry, X-ray crystallography, NMR or homology modeling methods and so is the theoretical understanding of protein-ligand interactions. As such, structure-based approaches to drug-design and in silico screening are becoming routine part of most modern lead discovery programs. Prioritization of compound libraries is an extremely important task that aims at the rapid identification of tight-binding ligands and ultimately new therapeutic compounds. These in silico approaches combined with other experimental methods facilitate the design of new medicines to treat cardiovascular, degenerative, infectious, and neoplastic diseases, among others. Here, we review key concepts and specific features of several selected ligand-receptor docking/scoring methods while several other topics pertaining to the field of in silico screening are reviewed in the following articles of this special issue of Current Protein and Peptide Science.     

低配位有机磷化学研究概况

长期以来,有机磷化学研究的核心内容主要集中在σ3和σ4的有机磷化合物及其衍生物方面,而低配位的有机磷化合物的研究则远远落后.本文简要综述了目前低配位的有机磷化合物σ1,λ1-亚膦烯、σ1,λ3-膦炔、σ2,λ3-膦烯和σ2,λ3-膦杂苯研究的最新进展,包括它们的合成及其在均相催化和材料等方面的应用.     

Lutetium bis(tetra-tert-butylphthalocyaninato): a superior redox probe to study the transfer of anions and cations across the water/nitrobenzene interface by means of square-wave voltammetry at the three-phase electrode

The redox properties of lutetium bis(tetra-tert-butylphthalocyaninato) (LBPC) have been studied in nitrobenzene that is deposited as a microfilm on the surface of highly oriented pyrolytic graphite electrodes. The behavior of the modified electrode, which is immersed in an aqueous electrolyte solution, is typical for the three-phase electrode (Scholz, F.; Komorsky-Lovri?, S.; Lovri?, M. Electrochem. Comm. 2000, 2, 112-118). LBPC can be both oxidized and reduced in one electron reversible processes. The oxidation and the reduction of LBPC at the graphite/nitrobenzene interface is accompanied by the transfer of anion or cation, respectively, from the aqueous phase into the organic layer. Thus, using LBPC as a redox probe for the three-phase electrode, the transfer of both anions and cations across the water/nitrobenzene interface can be studied in a single experiment. The hydrophobicity of LBPC is so high that it enables inspection of cations and anions with Delta (nb)(w) (G)(theta)(Cat+) < or = 43 kJ/mol and Delta (nb)(w) (G)(theta)(X-) < or = 50 kJ/mol, respectively. The direct transfer of Na(+) and Li(+) from water to nitrobenzene, mutually saturated, is achieved for the first time at a macroscopic water/nitrobenzene interface.     

Norbornane: an investigation into its valence electronic structure using electron momentum spectroscopy, and density functional and Green's function theories

We report on the results of an exhaustive study of the valence electronic structure of norbornane (C(7)H(12)), up to binding energies of 29 eV. Experimental electron momentum spectroscopy and theoretical Green's function and density functional theory approaches were all utilized in this investigation. A stringent comparison between the electron momentum spectroscopy and theoretical orbital momentum distributions found that, among all the tested models, the combination of the Becke-Perdew functional and a polarized valence basis set of triple-zeta quality provides the best representation of the electron momentum distributions for all of the 20 valence orbitals of norbornane. This experimentally validated quantum chemistry model was then used to extract some chemically important properties of norbornane. When these calculated properties are compared to corresponding results from other independent measurements, generally good agreement is found. Green's function calculations with the aid of the third-order algebraic diagrammatic construction scheme indicate that the orbital picture of ionization breaks down at binding energies larger than 22.5 eV. Despite this complication, they enable insights within 0.2 eV accuracy into the available ultraviolet photoemission and newly presented (e,2e) ionization spectra, except for the band associated with the 1a(2) (-1) one-hole state, which is probably subject to rather significant vibronic coupling effects, and a band at approximately 25 eV characterized by a momentum distribution of "s-type" symmetry, which Green's function calculations fail to reproduce. We note the vicinity of the vertical double ionization threshold at approximately 26 eV.     

Temporally and spatially heterogeneous distribution of mTHPC in a murine tumor observed by two-color confocal fluorescence imaging and spectroscopy in a whole-mount model

Efficient intratumor delivery of anticancer drugs and photosensitizers is an important factor in the success of chemotherapy and photodynamic therapy, respectively. Unfortunately, their adequate and uniform intratumor distribution is impeded by several physiological barriers and by binding to tissue components. Measurement of gross tumor drug accumulation is a routine method of investigating the uptake and clearance of chemotherapy agents and photosensitizers but tells little about their extravascular spatial distribution. We use whole-mount two-color confocal fluorescence imaging and imaging spectroscopy of unprocessed excised murine tumor fragments to investigate the intratumor distribution of the photosensitizer meso-tetrahydroxyphenyl chlorin (mTHPC) as a function of distance from blood vessels perfused with 0.2 mum diameter fluorescent microspheres. Significant mismatches between drug and perfused vasculature are caused by heterogeneities in tumor blood supply. We describe complex microscopic mTHPC gradients that reverse dramatically relative to the perfused vasculature with time after injection. This imaging technique can be applied to screen the dynamic intratumor distribution of other fluorescent photosensitizers and anticancer drugs.     

Propriétés électriques des gels aqueux d'amphiphile

Summary This paper deals with the calculation of electrical conductivity in soap-water-systems. Two models are discussed and compared with experimental data.

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Zusammenfassung In der vorliegenden Arbeit werden zwei Modelle zur Berechnung der Leitf?higkeit in Seifen-Wasser-Mischungen beschrieben und mit experimentellen Daten verglichen.

     

Solvation and dissociation of the carbanionic barium salt of the double 1,1′diphenylethylene in tetrahydrofuran

Mono- and dicarbanionic derivatives of 4,4bis(1-phenylethylene)1,1-biphenyl) (BPB): are prepared by addition of cumyl-barium or polystyryl-barium to BPB in tetrahydrofuran (THF). Spectroscopic and conductimetric measurements on monoadduct solutions were carried out in a temperature range from –105 to 25°C. At low temperature these solutions show a large spectral shift, due to the equilibrium between tight and solvent separated ion pairs. The thermodynamic parameters of this two step ion pair solvation were determined and the corresponding dissociation constant was found to be K _d =1×10^–6 mol-dm^–3 at 20°C. Once the first addition completed, the remaining double bond of the monoadduct seems to be less reactive than those of the original BPB. The diadduct has been prepared in the presence of an excess of cumyl-barium, and characterized spectroscopically.