Quest for the rings. In silico exploration of ring universe to identify novel bioactive heteroaromatic scaffolds.

Bioactive molecules only contain a relatively limited number of unique ring types. To identify those ring properties and structural characteristics that are necessary for biological activity, a large virtual library of nearly 600 000 heteroaromatic scaffolds was created and characterized by calculated properties, including structural features, bioavailability descriptors, and quantum chemical parameters. A self-organizing neural network was used to cluster these scaffolds and to identify properties that best characterize bioactive ring systems. The analysis shows that bioactivity is very sparsely distributed within the scaffold property and structural space, forming only several relatively small, well-defined "bioactivity islands". Various possible applications of a large database of rings with calculated properties and bioactivity scores in the drug design and discovery process are discussed, including virtual screening, support for the design of combinatorial libraries, bioisosteric design, and scaffold hopping.

Designing drugs on the internet? Free web tools and services supporting medicinal chemistry.

The drug discovery process is supported by a multitude of freely available tools on the Internet. This paper summarizes some of the databases and tools that are of particular interest to medicinal chemistry. These include numerous data collections that provide access to valuable chemical data resources, allowing complex queries of compound structures, associated physicochemical properties and biological activities to be performed and, in many cases, providing links to commercial chemical suppliers. Further applications are available for searching protein-ligand complexes and identifying important binding interactions that occur. This is particularly useful for understanding the molecular recognition of ligands in the lead optimization process. The Internet also provides access to databases detailing metabolic pathways and transformations which can provide insight into disease mechanism, identify new targets entities or the potential off-target effects of a drug candidate. Furthermore, sophisticated online cheminformatics tools are available for processing chemical structures, predicting properties, and generating 2D or 3D structure representations--often required prior to more advanced analyses. The Internet provides a wealth of valuable resources that, if fully exploited, can greatly benefit the drug discovery community. In this paper, we provide an overview of some of the more important of these and, in particular, the freely accessible resources that are currently available.

Estimation of pKa for druglike compounds using semiempirical and information-based descriptors.

A pragmatic approach has been developed for the estimation of aqueous ionization constants (pKa) for druglike compounds. The method involves an algorithm that assigns ionization constants in a stepwise manner to the acidic and basic groups present in a compound. Predictions are made for each ionizable group using models derived from semiempirical quantum chemical properties and information-based descriptors. Semiempirical properties include the partial charge and electrophilic superdelocalizabilty of the atom(s) undergoing protonation or deprotonation. Importantly, the latter property has been extended to allow predictions to be made for multiprotic compounds, overcoming limitations of a previous approach described by Tehan et al. The information-based descriptions include molecular-tree structured fingerprints, based on the methodology outlined by Xing et al., with the addition of 2D substructure flags indicating the presence of other important structural features. These two classes of descriptor were found to complement one another particularly well, resulting in predictive models for a range of functional groups (including alcohols, amidines, amines, anilines, carboxylic acids, guanidines, imidazoles, imines, phenols, pyridines, and pyrimidines). A combined RMSE of 0.48 and 0.81 was obtained for the training set and an external test set compounds, respectively. The predictive models were based on compounds selected from the commercially available BioLoom database. The resultant speed and accuracy of the approach has also enabled the development of Web application on the Novartis intranet for pKa prediction.

Calculation of intersubstituent similarity using R-group descriptors.

This paper discusses the calculation of the similarities between pairs of substituents on ring systems. An R-group descriptor characterizes the distribution of some atom-based property, such as elemental type or partial atomic charge, at increasing numbers of bonds distant from the point of substitution on the parent ring. The similarity between a pair of descriptors is then calculated by a comparison of the corresponding property vectors. Experiments with the BIOSTER database demonstrate the ability of such similarity measures to discriminate between bioisosteric and nonbioisosteric functional groups.

8-Aryl xanthines potent inhibitors of phosphodiesterase 5.

In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.