A hierarchical screening methodology for physicochemical/ADME/Tox profiling.

Full integration of pharmaceutical profiling into pharmaceutical lead selection and optimisation requires that complete sets of unequivocal data be available at the time compound design or advancement decisions are made. As the productivity of chemical synthesis expands, and the breadth of profiling assays grow in scope, physicochemical/ADME/Tox laboratories are being challenged to produce ever more data to support an accelerating decision cycle. This article focuses on the challenges of increasing preclinical profiling productivity while managing lower accuracy higher throughput data streams to preserve confidence in decision making.

Avoiding physicochemical artefacts in early ADME-Tox experiments.

Recent literature has highlighted the importance of fundamental physicochemical properties in HTS and ADME-Tox: high lipophilicity, low dimethyl sulfoxide solubility, low aqueous solubility, aggregation and nonspecific binding to proteins and phospholipids. Unless carefully controlled for, each of these artefacts can confound individual ADME-Tox results and their interpretation on aggregate. This article reviews the impact of these phenomena and suggests experimental strategies for minimizing the magnitude and frequency of these artefacts without compromising the essential speed of the experimental process.

Exhaustive enumeration of protein conformations using experimental restraints.

We present an efficient new algorithm that enumerates all possible conformations of a protein that satisfy a given set of distance restraints. Rapid growth of all possible self-avoiding conformations on the diamond lattice provides construction of alpha-carbon representations of a protein fold. We investigated the dependence of the number of conformations on pairwise distance restraints for the proteins crambin, pancreatic trypsin inhibitor, and ubiquitin.

Carotid surgery under locoregional anaesthesia. Description of technique and results of our first 100 consecutive operations.

In a 28-month-period 100 consecutive carotid operations were performed on 91 patients under locoregional anaesthesia. The indications were 37 TIAs, 16 recovered strokes, 12 cases presenting with amaurosis fugax, eight with vertigo and 27 patients with severe but still asymptomatic stenosis. In 20 cases a shunt had to be used.

Pseudodihedrals: simplified protein backbone representation with knowledge-based energy.

Pairwise contact energies do not explicitly take protein secondary structure into account, and so provide an incomplete description of conformational energy. In order to construct a Hamiltonian that specifically relates to protein backbone conformations, a simplified backbone angle is used. The pseudodihedral angle (the torsion angle between planes defined by 4 consecutive alpha-carbon atoms) provides a simplified backbone representation and continues to manifest information about secondary-structure elements: the pseudo-Ramachandran plot contains helical and sheetlike regions.