Comparative performance assessment of the conformational model generators omega and catalyst: a large-scale survey on the retrieval of protein-bound ligand conformations

In continuation of our studies to evaluate the ability of various conformer generators to produce bioactive conformations, we present the extension of our work on the analysis of Catalyst's conformational subsampling algorithm in a comparative evaluation with OpenEye's currently updated tool Omega 2.0. Our study is based on an enhanced test set of 778 drug molecules and pharmacologically relevant compounds extracted from the Protein Data Bank (PDB). We elaborated protocols for two common conformer generation use cases and applied them to both programs: (i) high-throughput settings for processing large databases and (ii) high-quality settings for binding site exploration or lead structure refinement. While Catalyst is faster in the first case, Omega 2.0 better reproduces the bound ligand conformations from the PDB in less time for the latter case.     

Pharmacophore modeling and in silico screening for new P450 19 (aromatase) inhibitors

Cytochrome P450 19 (P450 19, aromatase) constitutes a successful target for the treatment of breast cancer. This study analyzes chemical features common to P450 19 inhibitors to develop ligand-based, selective pharmacophore models for this enzyme. The HipHop and HypoRefine algorithms implemented in the Catalyst software package were employed to create both common feature and quantitative models. The common feature model for P450 19 includes two ring aromatic features in its core and two hydrogen bond acceptors at the ends. The models were used as database search queries to identify active compounds from the NCI database.     

Unordered and ordered sample from dirichlet distribution

Consider the random Dirichlet partition of the interval inton fragments with parameter π>0. Explicit results on the statistical structure of its size-biased permutation are recalled, leading to (unordered) Ewens and (ordered) Donnelly-Tavaré-Griffiths sampling formulae from finite Dirichlet partitions. We use these preliminary statistical results on frequencies distribution to address the following sampling problem: what are the intervals between new sampled categories when sampling is from Dirichlet populations? The results obtained are in accordance with the ones found in sampling theory from random proportions with GEM(γ) distribution. These can be obtained from Dirichlet model when considering the Kingman limitn↑∞, π↓0 whilenπ=γ>0.     

A deeper insight into direct trifluoromethoxylation with trifluoromethyl triflate

Commercially available fluorides (silver fluoride and n-tetrabutylammonium triphenyldifluorosilicate), combined with TFMT, allow a simple generation, in situ, of silver and n-tetrabutylammonium trifluoromethoxides which were able to react with electrophilic substrates. Silver trifluoromethoxide, which is usually more efficient than n-tetrabutylammonium trifluoromethoxide, converts, under mild conditions, primary aliphatic bromides and iodides, as well as primary and secondary benzylic or allylic bromides to the corresponding trifluoromethoxylated compounds. Several trifluoromethyl ethers, which could be valuable building-blocks, were prepared in such a way.     

Large Deviations for the Yang-Mills Measure on a Compact Surface

We prove the first mathematical result relating the Yang-Mills measure on a compact surface and the Yang-Mills energy. We show that, at the small volume limit, the scaled Yang-Mills measures satisfy a large deviation principle with a rate function which is expressed in a simple and natural way in terms of the Yang-Mills energy.     

On the uniqueness of the solution of the two‐dimensional Navier–Stokes equation with a Dirac mass as initial vorticity

We propose two different proofs of the fact that Oseen's vortex is the unique solution of the two‐dimensional Navier–Stokes equation with a Dirac mass as initial vorticity. The first argument, due to C. E. Wayne and the second named author, is based on an entropy estimate for the vorticity equation in self‐similar variables. The second proof is new and relies on symmetrization techniques for parabolic equations. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

On Entropic Reduction of Fluctuations

We point out that there is no general relation between ground state degeneracy and finite-temperature fluctuations for tilted interfaces.     

Sensing a binding event through charge transport variations using an aromatic oligoamide capsule

The selective binding properties of a 13-mer oligoamide foldamer capsule composed of 4 different aromatic subunits are reported. The capsule was designed to recognize dicarboxylic acids through multiple-point interactions owing to a combination of protonation/deprotonation events, H-bonding, and geometrical constraints imparted by the rigidity of the foldamer backbone. Compared to tartaric acid, binding of 2,2-difluorosuccinic acid or 2,2,3,3-tetrafluorosuccinic acid resulted in symmetry breaking due to deprotonation of only one of the two carboxylic acid groups of the encapsulated species as shown by NMR studies in solution and by single-crystal X-ray diffraction in the solid state. An analogous 14-mer foldamer capsule terminated with a thiol anchoring group was used to probe the complexation event in self-assembled monolayers on Au substrates. Ellipsometry and polarization-modulation infrared absorption-reflection spectroscopy studies were consistent with the formation of a single molecule layer of the foldamer capsule oriented vertically with respect to the surface. The latter underwent smooth complexation of 2,2-difluorosuccinic acid with deprotonation of one of the two carboxylic acid groups. A significant (80-fold) difference in the charge transport properties of the monolayer upon encapsulation of the dicarboxylic acid was evidenced from conducting-AFM measurements (S = 1.1 × 10⁻⁹vs. 1.4 × 10⁻¹¹ ohm⁻¹ for the empty and complexed capsule, respectively). The modulation in conductivity was assigned to protonation of the aromatic foldamer backbone.

Conductance through a monolayer of a helical foldamer host was found to vary by 80-fold depending on the presence or the absence of a guest in the host''s cavity.