OptiDock: virtual HTS of combinatorial libraries by efficient sampling of binding modes in product space

Products from combinatorial libraries generally share a common core structure that can be exploited to improve the efficiency of virtual high-throughput screening (vHTS). In general, it is more efficient to find a method that scales with the total number of reagents (Sigma growth) rather with the number of products (Pi growth). The OptiDock methodology described herein entails selecting a diverse but representative subset of compounds that span the structural space encompassed by the full library. These compounds are docked individually using the FlexX program (Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. J. Mol. Biol. 1995, 251, 470-489) to define distinct docking modes in terms of reference placements for combinatorial core atoms. Thereafter, substituents in R-cores (consisting of the core structure substituted at a single variation site) are docked, keeping the core atoms fixed at the coordinates dictated by each reference placement. Interaction energies are calculated for each docked R-core with respect to the target protein, and energies for whole compounds are calculated by finding the reference core placement for which the sum of corresponding R-core energies is most negative. The use of diverse whole compounds to define binding modes is a key advantage of the protocol over other combinatorial docking programs. As a result, OptiDock returns better-scoring conformers than does serially applied FlexX. OptiDock is also better able to find a viable docked pose for each library member than are other combinatorial approaches.     

Determination of isotopic thorium in biological samples by combined alpha-spectrometry and neutron activation analysis

The determination of isotopic thorium by alpha-spectrometric methods is a routine practice for bioassay and environmental measurement programs. Alpha-spectrometry has excellent detection limits (by mass) for all isotopes of thorium except²³²Th due to its extremely long half-life. This paper reports a pre-concentration neutron activation analysis (PCNAA) method for²³²Th that may be performed following alpha-spectrometry if a suitable source preparation material is utilized. Human tissues and other samples were spiked with²²⁹Th and the thorium was isolated from the sample using ion exchange chromatography. The thorium was then electrodeposited from a sulfate-based medium onto a vanadium planchet, counted by alpha-spectrometry, and then analyzed for²³²Th by neutron activation analysis. The radiochemical yield was determined from the alpha-spectrometric method. Detection limits for²³²Th by this PCNAA method are approximately 50 times lower than achieved by alphaspectrometry.     

Models to predict solubility in ternary solvents based on sub-binary experimental data

The capability of the extended forms, of two well established cosolvency models, i.e. the combined nearly ideal binary solvent/Redlich-Kister equation and the modified Wilson model, used to predict the solute solubility in non-aqueous ternary solvent mixtures is presented. These predictions are based on the measured solubilities of anthracene in binary solvent mixtures. As a result the values of average percent deviations were less than 2% for the anthracene solubility in ternary mixtures. This work was also extended to other cosolvency models, ie. the extended Hildebrand solubility approach and the mixture response surface method, which are also commonly used for correlating solubility data in ternary solvents. The accuracy of the models is compared with each other and also with a published solubility model for ternary mixtures. The results illustrate that all models produced comparable accuracy.     

Electronic structures of some olefins and their radical cations

CNDO/2 calculations of the electronic properties of the series of isomeric butenes and pentenes yield ionization potentials which reproduce the observed trends. These are interpreted in terms of the charge distribution effects of the alkyl groups.

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Zusammenfassung CNDO/2 Rechnungen für die Butan- und Penten-Isomeren ergeben die richtigen Trends für die Ionisierungspotentiale. Sie werden im Zusammenhang mit der Änderung der Ladungsverteilung infolge Methylsubstitution diskutiert.

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Résumé Des calculs CNDO/2 des propriétés électroniques des séries d'isomères du butène et du pentène fournissent des potentiels d'ionisation qui reproduisent les tendances observées. Les distributions de charge calculées pour les molécules sont utilisées pour interpréter les propriétés observées en termes d'effet du substituant alkyle.

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Presented in part at the Eighth Theoretical Chemistry Symposium held at the Batelle Institute, Geneva, Switzerland; March 26–30, 1972.     

Template-directed self-assembly of 10-microm-sized hexagonal plates

This article presents a strategy for the fabrication of ordered microstructures using concepts of design inspired by molecular self-assembly and template-directed synthesis. The self-assembling components are 4-microm-thick hexagonal metal plates having sides 10 microm in length ("hexagons"), and each template consists of a 4-microm-thick circular metal plate surrounding a central cavity, the perimeter of which is complementary in shape to the external edges of a two-dimensional, close-packed array of hexagons. The hexagons and templates (collectively, "pieces") were fabricated via standard procedures and patterned into hydrophobic and hydrophilic regions using self-assembled monolayers (SAMs). Templated self-assembly occurs in water through capillary interactions between thin films of a nonpolar liquid adhesive coating the hydrophobic faces of the pieces. The hexagons tile the cavities enclosed by the templates, and the boundaries of the cavities determine the sizes and shapes of the assemblies. Curing the adhesive with ultraviolet light furnishes mechanically stable arrays having well-defined morphologies. By allowing control over the structures of the resulting aggregates, this work represents a step toward the development of practical methods for microfabrication based on self-assembly.     

Level decay and orientational kinetics of the rhodamine B monomer and dimer

The population kinetics and the rotational diffusion of the rhodamine B monomer and dimer were measured by using picosecond pulses from a mode-locked Nd : YAG laser to induce and time resolve the concentration-dependent transient absorption saturation of various aqueous solutions of this organic dye.     

Aldol reactions of a cyclobutanone enolate

Addition of an aldehyde and zinc chloride to a cyclobutanone enolate, prepared by the reaction of an α-chlorocyclobutanone with dimethylcopperlithium, gave an aldol adduct in good yield.     

Environmentally “controlled collapse” of the 4f orbital in Cs

Electron-energy loss spectroscopy has been used to investigate excitations near theN ₄₅ edges of Cs metal and Cs oxide at primary electron energiesE _p between 200 and 2000 eV. The fine structures in the spectra show pronounced differences between the metal and the oxide. AtE _p=2000 eV the 4d ⁹ 4f collapsed multiplets and 4d6p like transitions appear with greater intensity in the oxide, and a strong optically allowed component at 93 eV loss energy, which we attribute to a 4d ⁹ 4f ¹ P ₁ ⁰ exciton, is also seen much more clearly. At lowerE _p the non-dipole oscillator strength in the metal is spread over a wider energy range than in the oxide. With the aid of atomic structure calculations these results are interpreted in terms of differential partial collapse of the 4f orbital in the metal and the oxide, due to a combination of reduced screening and ionic potential cage effects.     

Application of ESCA to polymer chemistry. XVI. Electron mean free paths as a function of kinetic energy in polymeric films determined by means of ESCA

Electron mean free paths as a function of kinetic energy have been measured by the substrate overlayer technique for in situ-polymerized films of poly(p-xylylene) and the monochloro- and monobromo-substituted derivatives. The results are compared with previous estimates of mean free paths available in the literature for organic materials. Comparison is also drawn with corresponding experimental data for typical metals and semiconductors, and it is shown that organic polymers fit into a consistent picture which may be rationalized on the basis of existing theory. For electrons of kinetic energy ～969 eV, ～1170 eV, 1202 eV, and 1403 eV, mean free paths of ～14 Å, ～22 Å, ～23 Å, and ～29 Å, respectively, are obtained for the poly(p-xylylene) polymer films studied in this work.     

A highly enantioselective conjugate reduction of 3-arylinden-1-ones using bakers' yeast for the preparation of (S)-3-arylindan-1-ones

[formula: see text] The bakers' yeast reduction of 3-(1,3-benzodioxol-5-yl)-6-propoxy-1H-inden-1-one 4 has been shown to give (S)-3-(1,3-benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-indan-1-one 6 in 65% yield with high enantioselectivity (> 99.0% ee), a key intermediate for the synthesis of the endothelin receptor antagonist SB 217242. In addition, the substituted 3-arylinden-1-ones 10a-e gave equally high enantioselectivity for the 3-arylindan-1-one products 13a-e. Mechanistic studies of the reaction indicate the operative pathway to be an asymmetric conjugate reduction, wherein the hydride transfer from NAD(P)H occurs from the Re-face of the indenone substrate.