Mining for bioactive scaffolds with scaffold networks: improved compound set enrichment from primary screening data

Identification of meaningful chemical patterns in the increasing amounts of high-throughput-generated bioactivity data available today is an increasingly important challenge for successful drug discovery. Herein, we present the scaffold network as a novel approach for mapping and navigation of chemical and biological space. A scaffold network represents the chemical space of a library of molecules consisting of all molecular scaffolds and smaller "parent" scaffolds generated therefrom by the pruning of rings, effectively leading to a network of common scaffold substructure relationships. This algorithm provides an extension of the scaffold tree algorithm that, instead of a network, generates a tree relationship between a heuristically rule-based selected subset of parent scaffolds. The approach was evaluated for the identification of statistically significantly active scaffolds from primary screening data for which the scaffold tree approach has already been shown to be successful. Because of the exhaustive enumeration of smaller scaffolds and the full enumeration of relationships between them, about twice as many statistically significantly active scaffolds were identified compared to the scaffold-tree-based approach. We suggest visualizing scaffold networks as islands of active scaffolds.     

Theory of carbon monoxide chemisorption on transition metals

An Anderson formalism including overlap is used to treat the chemisorption of carbon monoxide on the transition metals Cu, Ni and Pd. According to the generally accepted scheme only coupling of the 2π¹- and 5σ-orbitals of CO to the metallic d-states is regarded. The wave functions of the metal surface are approximated by a linear combination of atomic d-orbitals, which are oriented in such a manner that maximum overlap with the 2π¹-orbital of CO is achieved. The error involved in this procedure is absorbed into the only adjustable parameter B. Predictions are made for the electronic structure, i.e. the chemisorption levels and occupation numbers. Comparison with results of photoelectron spectroscopy, energy loss spectroscopy and infrared experiments is encouraging. The variation of adsorption energy with geometric location, crystallographic orientation and nature of the substrate metal is extensively treated and compared with experiment. It was possible for example to predict correctly the structure models derived from LEED data and the changes in adsorption energy associated with structural modifications due to varying coverage.     

Interaction of NO and O2 with Pd(111) surfaces. I.

The adsorption of NO on Pd(111) was studied by means of LEED, UPS and thermal desorption measurements. Non-dissociative adsorption is characterized by additional maxima in the photomission spectra at 2.6, 9.2 and 14.6 eV below the Fermi level originating from chemisorption levels which are derived from the highest occupied molecular orbitais of NO. Thermal desorption takes place from three distinct states (α, β and γ) corresponding to binding energies of about 15, 17 and 31 kcal/mole, respectively, with about equal populations. The α-state is associated with a 2 × 2 LEED pattern and the β-state with a c4 × 2 structure, whereas the γ-state corresponds to disordered adsorption at low coverages. Plausible structure models are proposed for the ordered structures with θ = 0.75 for the α-state and θ = 0.5 for the β-state. The strong decrease of the adsorption energy is explained in terms of pronounced short-range repulsive interactions between neighbouring adsorbate molecules.     

Interaction of NO and O2 with Pd(111) surfaces. II

At least three different types of oxygen atoms may be present in the surface region of Pd(111) which may be distinguished by their thermal, chemical, structural and electronic properties. Exposure to O₂ at low temperatures causes the formation of 2 × 2 and $\text{3}\text{×}\text{3}\text{R30°}$ structures from chemisorbed oxygen, the latter being probably stabilized by small amounts of H_ab or CO_ab on the surface. The initial sticking coefficient was estimated to be about s₀ ≈ 0.3, the adsorption energy ~55 kcal/mole. The photoelectron spectrum exhibits an additional maximum at 5 eV below E_F. During thermal desorption dissolution of oxygen in the bulk strongly competes; on the other hand absorbed oxygen may diffuse to the surface giving rise to high temperature peaks in the flash desorption spectra. High temperature (~1000 K) treatment of the sample with O₂ causes the formation of a more tightly bound surface species also characterized by a 2 × 2 LEED pattern which is chemically rather stable and which is considered to be a transition state to PdO. The latter compound is only formed by interaction with NO at about 1000 K via the reaction $\text{Pd}\text{+}\text{NO}\text{→}\text{PdO}\text{+}\text{1}\text{2N}{}_2$ which offers a rather high “virtual” oxygen pressure. This reaction leads to drastic changes of the photoelectron spectrum and is also identified within the LEED pattern.     

Order-disorder transitions in a chemisorbed system: Hydrogen on Ni (111)

Atomic hydrogen chemisorbed on a Ni (111) surface forms at coverages between 0.3 and 0.6 an ordered 2 × 1-structure as observed by low energy electron diffraction (LEED). The intensity of the fractional-order LEED spots was measured at different coverages as a function of temperature. Continuous order-disorder transitions are found, the maximum transition temperature (270 K) being at θ = 0.5. The phase diagram, however, is asymmetric with respect to this coverage and can therefore presumably not be explained on the basis of (independent) pairwise interactions.     

Non-equilibrium surface phase transitions during the catalytic oxidation of CO on Pt(100)

Isothermal low-pressure oscillations of the rate of catalytic CO oxidation on a Pt(100) surface could be established under appropriate conditions and were monitored through the accompanying periodic variation of the work function. Parallel observations by the Video-LEED technique demonstrated that these oscillations are associated with periodic transformations of the (long-range) surface structure from the reconstructed hex to the 1 × 1 phase and back, which is caused by varying surface concentrations of the reacting particles.