Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files

High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.     

Synthesis and characterization of homo- and heterodinuclear M(II)-M'(III) (M(II) = Mn or Fe, M'(III) = Fe or Co) mixed-valence supramolecular pseudo-dimers. The effect of hydrogen bonding on spin state selection of M(II)

Reaction of H(3)L(1), the Schiff base condensate of tris(2-aminoethyl)amine with three equivalents of 5-methyl-1H-pyrazole-3-carboxaldehyde, with manganese(II)perchlorate or iron(II)tetrafluoroborate results in the isolation of [MH(3)L(1)]X(2) (M = Mn and X = ClO(4) and M = Fe and X = BF(4)). These complexes are high spin d(5) and d(6), respectively, as inferred from the long M-N bond distances obtained by single crystal X-ray diffraction for both and variable temperature magnetic susceptibility and M?ssbauer spectroscopy for the iron complex. Aerobic treatment of a solution of [CoH(3)L(1)](2+) with three equivalents of potassium hydroxide produced [CoL(1)]. Homonuclear pseudo-dimers were prepared by the aerobic reaction of [FeH(3)L(1)](BF(4))(2) with 1.5 equivalents of potassium hydroxide to give {[FeH(1.5)L(1)](BF(4))}(2) or by the metathesis reaction of [FeH(2)L(1)][FeHL(1)](ClO(4))(2) with sodium hexafluorophosphate to give [FeH(3)L(1)][FeL(1)](PF(6))(2). The complexes were characterized by EA, IR, ESI-MS, variable temperature single crystal x-ray diffraction and M?ssbauer spectroscopy. The iron(III) atom is low spin while the iron(II) atom is spin crossover. Heteronuclear pseudo-dimers were prepared by the 1:1 reaction of [FeH(3)L(1)](BF(4))(2) or [MnH(3)L(1)](ClO(4))(2) with [CoL(1)]. [MH(3)L(1)][CoL(1)](X)(2) (M = Fe and X = BF(4) or M = Mn and X = ClO(4)), were characterized by IR, EA, variable temperature single crystal X-ray diffraction and M?ssbauer spectroscopy in the iron case. The data support a spin crossover and high spin assignment for the iron(II) and manganese(II), respectively. DFT calculations demonstrate that the spin state of the iron(II) atom in {[FeH(3)L(1)][FeL(1)]}(2+) changes from high spin to low spin as the iron(II)-iron(III) distance decreases. This is supported by experimental results and is a result of hydrogen bonding interactions which cause a significant compression of the M(II)-N(pyrazole) bond distances.     

Filament architectures in AC conductors: the influence of intergrowths

Filament isolation is an extremely important factor in multi-filamentary conductors, and attempts have been made to achieve this by incorporating a resistive oxide sheath around individual filaments. However, filament-bridging intergrowths have been observed in conductors with and without the resistive sheath. We present magnetisation results on BSCCO-2223/Ag conductors with different filament configurations, and analyse the data taking into account the effects of magnetic coupling between filaments. All samples studied display some degree of filament bridging.     

Restricted intramolecular vibrational relaxation in polyatomics and laser selective effects

A theory for unimolecular dissociation applicable to selective laser excitation is presented. Expressions for lifetimes, yields, and product fragment translational energy distributions are given as a function of IVR rate. We analyze an experiment purporting to “ demonstrate” rapid IVR.     

Čebyšev mixing and harmonic oscillator models

We exhibit a simple variable pitch helix model which shows that the “chaotic” behavior of ?eby?ev iterations is an illusion of dimensional projection. As a consequence the stroboscopic images of the motion of a simple harmonic oscillator, recorded at the times 2ⁿt (n = 0, 1, 2, …), reproduce the mixing. This power law of time evolution may be used to generate other types of mixing transformations.     

Comparisons of the RPA,SCRPA, Tamm–Dancoff,and full CI methods by analysis of their transition density matrices,oscillator strengths,and energy moments of oscillator strengths for the electric dipole transitions from the ground state of the B+ ion (frozen K-shell model)

The RPA, SCRPA , Tamm–Dancoff, and full CI methods are compared by analyzing their transition density matrices, oscillator strengths, and energy moments of oscillator strengths for the ¹S_ground – ¹P_odd transitions of the 4-electron B⁺ ion in the frozen K-shell approximation. It is found that the RPA gives transition density matrices that are aligned nearly as well as possible along those of the full CI , but have vector lengths that are significantly too long. The corresponding transition energies are significantly too small. These errors compensate to give oscillator strengths for the dominant transition that, for all forms of the oscillator strength, are within 1.6% of the corresponding full CI values. The SCRPA gives better transition density matrices than the RPA , but poorer oscillator strengths. The Tamm-Dancoff approximation gives very good values for the mixed length-velocity form of the oscillator strength. The RPA gives a static electric dipole polarizability that is nearly 20% larger than that of the full CI . The SCRPA gives a value 15% smaller than—and the Tamm-Dancoff approximation gives a mixed length-velocity value that is 11% larger than—that of the full CI . Other energy moments of oscillator strengths are also reported. Certain other approximations related to the RPA and the SCRPA are reported as well.     

A pyrolysis/gas chromatographic method for the determination of hydrogen in solid samples

A method is described for the determination of hydrogen in solid samples. The sample is heated under vacuum after which the evolved gases are separated by gas chromatography with a helium ionization detector. The system is calibrated by injecting known amounts of hydrogen, as determined manometrically. The method, which is rapid and reliable, was checked for a variety of lunar soils; the limit of detection is about 10 ng of hydrogen.