Tautomer Standardization in Chemical Databases: Deriving Business Rules from Quantum Chemistry.

Databases of small, potentially bioactive molecules are ubiquitous across the industry and academia. Designed such that each unique compound should appear only once, the multiplicity of ways in which many compounds can be represented means that these databases require methods for standardizing the representation of chemistry. This is commonly achieved through the use of "Chemistry Business Rules", sets of predefined rules that describe the "house style" of the database in question.

G-protein-coupled receptor dynamics: dimerization and activation models compared with experiment.

Our previously derived models of the active state of the β2-adrenergic receptor are compared with recently published X-ray crystallographic structures of activated GPCRs (G-protein-coupled receptors). These molecular dynamics-based models using experimental data derived from biophysical experiments on activation were used to restrain the receptor to an active state that gave high enrichment for agonists in virtual screening. The β2-adrenergic receptor active model and X-ray structures are in good agreement over both the transmembrane region and the orthosteric binding site, although in some regions the active model is more similar to the active rhodopsin X-ray structures.

Quantitatively interpreted enhanced inhibition of cytochrome P450s by heteroaromatic rings containing nitrogen.

It has been known for a long time that certain substructures bind to the heme iron in cytochromes P450. Detection of spectroscopic changes and crystal structures of protein ligand complexes have provided qualitative evidence, including for aromatic nitrogen-containing ligands. Compounds containing these same substructures are more likely to inhibit cytochrome P450s than expected due to lipophilicity.

Toward the active conformations of rhodopsin and the beta2-adrenergic receptor.

Using sets of experimental distance restraints, which characterize active or inactive receptor conformations, and the X-ray crystal structure of the inactive form of bovine rhodopsin as a starting point, we have constructed models of both the active and inactive forms of rhodopsin and the beta2-adrenergic G-protein coupled receptors (GPCRs). The distance restraints were obtained from published data for site-directed crosslinking, engineered zinc binding, site-directed spin-labeling, IR spectroscopy, and cysteine accessibility studies conducted on class A GPCRs. Molecular dynamics simulations in the presence of either "active" or "inactive" restraints were used to generate two distinguishable receptor models.