Selection of fragments for kinase inhibitor design: decoration is key.

In fragment-based screening, the choice of the best suited fragment hit among the detected hits is crucial for success. In our study, a kinase lead compound was fragmented, the hinge-binding motif extracted as a core fragment, and a minilibrary of five similar compounds with fragment-like properties was selected from our proprietary compound database. The structures of five fragments in complex with transforming growth factor β receptor type 1 kinase domain were determined by X-ray crystallography.

A normal mode-based geometric simulation approach for exploring biologically relevant conformational transitions in proteins.

A three-step approach for multiscale modeling of protein conformational changes is presented that incorporates information about preferred directions of protein motions into a geometric simulation algorithm. The first two steps are based on a rigid cluster normal-mode analysis (RCNMA). Low-frequency normal modes are used in the third step (NMSim) to extend the recently introduced idea of constrained geometric simulations of diffusive motions in proteins by biasing backbone motions of the protein, whereas side-chain motions are biased toward favorable rotamer states.

Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay.

Preventing the formation of insoluble polyglutamine containing protein aggregates in neurons may represent an attractive therapeutic strategy to ameliorate Huntington's disease (HD). Therefore, the ability to screen for small molecules that suppress the self-assembly of huntingtin would have potential clinical and significant research applications. We have developed an automated filter retardation assay for the rapid identification of chemical compounds that prevent HD exon 1 protein aggregation in vitro.

Discriminating between drugs and nondrugs by prediction of activity spectra for substances (PASS).

Using the computer system PASS (prediction of activity spectra for substances), which predicts simultaneously several hundreds of biological activities, a training set for discriminating between drugs and nondrugs is created. For the training set, two subsets of databases of drugs and nondrugs (a subset of the World Drug Index, WDI, vs the Available Chemicals Directory, ACD) are used. The high value of prediction accuracy shows that the chemical descriptors and algorithms used in PASS provide highly robust structure-activity relationships and reliable predictions.

LIGSITE: automatic and efficient detection of potential small molecule-binding sites in proteins.

LIGSITE is a new program for the automatic and time-efficient detection of pockets on the surface of proteins that may act as binding sites for small molecule ligands. Pockets are identified with a series of simple operations on a cubic grid. Using a set of receptor-ligand complexes we show that LIGSITE is able to identify the binding sites of small molecule ligands with high precision.

The comparison of geometric and electronic properties of molecular surfaces by neural networks: application to the analysis of corticosteroid-binding globulin activity of steroids.

It is shown how a self-organizing neural network such as the one introduced by Kohonen can be used to analyze features of molecular surfaces, such as shape and the molecular electrostatic potential. On the one hand, two-dimensional maps of molecular surface properties can be generated and used for the comparison of a set of molecules. On the other hand, the surface geometry of one molecule can be stored in a network and this network can be used as a template for the analysis of the shape of various other molecules.

Synthesis and dopaminergic activity of some 3-(1,2,3,6-tetrahydro-1-pyridylalkyl)indoles. A novel conformational model to explain structure-activity relationships.

The synthesis and dopaminergic properties of a novel type of dopamine agonist is described. The number and kind of essential structural elements differ significantly from that of the rigid apomorphine-type dopamine agonists. Using standard molecular modeling techniques, a conformational model is developed proposing a U-shaped conformation which might be energetically preferred through aromatic pi-pi-interactions between both of the electron rich aromatic structural elements of this class of compounds.

Conformation-based design of two cyclic physalaemin analogues.

Two new cyclic analogues of physalaemin were designed on the basis of the conformation found in DMSO solution. Glp-Ala-cyclo(-Asp-Pro-Asn-Lys-)-Phe-Tyr-Gly-Leu-Met-NH2 (1) was synthesized by cyclization of physalaemin. In 2 the Asp residue was replaced by Glu.

Synthesis, conformational studies, and molecular dynamics calculations of two cyclic tetrapeptides with 17- and 18-membered rings.

Two cyclic tetrapeptides [Boc-cyclo(-Xxx-Pro-Asn-Lys-)OMe (Xxx = Asp or Glu)] were synthesized and investigated by NMR spectroscopy. They were designed in order to mimic the salt bridge found in physalaemin. Isomers of the urethane bond were observed in DMSO solution.

High state of order of isolated bacterial lipopolysaccharide and its possible contribution to the permeation barrier property of the outer membrane.

The conformational properties of the isolated S form of Salmonella sp. lipopolysaccharide (LPS), of Re mutant LPS, and of free lipid A were investigated by using X-ray diffraction and conformational energy calculations. The data obtained showed that LPS in a dried, in a hydrated, and probably also in an aqueous dispersion state is capable of forming bilayered lamellar arrangements similar to phospholipids.

Conformational and topological aspects of the three-dimensional architecture of bacterial peptidoglycan.

An atomic model of the conformation of peptidoglycan was taken as the basis for an analysis of packing patterns of the peptidoglycan strands in two- and three-dimensional arrangements. For the sake of clarity, glycan strands were approximated by cylindrical rods around which a continuous helix of possible peptide cross-linkage sites was arranged. Using the packing patterns obtained, several important properties of the murein network could be explained.

A new proposal for the primary and secondary structure of the glycan moiety of pseudomurein. Conformational energy calculations on the glycan strands with talosaminuronic acid in 1C conformation and comparison with murein.

Using the method of conformational energy calculations, favoured conformations of a pseudomurein sugar strand built up from beta 1,3-linked N-acetyl-D-glucosamine and N-acetyl-L-talosaminuronic acid were obtained. Such a completely beta 1,3-linked polysaccharide primary structure, although contrasting with the originally proposed alternating beta 1,3-alpha 1,3-linked structure [König, H., Kandler, O.

Structural studies on the bacterial cell wall peptidoglycan pseudomurein. I. Conformational energy calculations on the glycan strands in C1 conformation and comparison with murein.

Conformational energy calculations have been used to explore the conformations which may be realized for the sugar moiety of murein and pseudomurein. For the building blocks of the pseudomurein sugar strands, i.e.

Study of the Zn-containing DD-carboxypeptidase of Streptomyces albus G by small-angle X-ray scattering in solution.

Study of the Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase of Streptomyces albus G by small-angle X-ray scattering in solution yielded the following molecular parameters: radius of gyration R = 1.82 +/- 0.05 nm; largest diameter D = 5.

Infrared spectroscopy, a tool for probing bacterial peptidoglycan. Potentialities of infrared spectroscopy for cell wall analytical studies and rejection of models based on crystalline chitin.

Infrared spectroscopic measurements are used to obtain insights into the three-dimensional architecture of peptidoglycan (murein), the rigid component of almost all bacterial cell walls. The infrared spectra of various types of peptidoglycans (including all chemotypes and examples of the so called A and B groups) were compared to each other and to those obtained from crystalline chitin. All peptidoglycans investigated exhibited very similar infrared spectra.

Conformational energy calculation on the peptide part of murein.

Conformational energy calculations have been carried out on N-acetyl-L-alanyl-D-gamma-glutamyl-L-lysyl-D-alanyl-D-alanine as a model of the peptide moiety of peptidoglycan. Although many conformations were of comparable energy, particular favoured conformations were selected by assuming conformational similarity between the pentapeptide and the tetrapeptide found during biosynthesis subsequent to the cross-linking of the peptide chains in murein. The common feature of these conformations, which include the global minimum of the pentapeptide, is a ring-shaped backbone.