A computational method to rapidly assess and visualize the diversity in molecular shape associated with a given compound set has been developed. Normalized ratios of principal moments of inertia are plotted into two-dimensional triangular graphs and then used to compare the shape space covered by different compound sets, such as combinatorial libraries of varying size and composition. We have further developed a computational method to analyze interset similarity in terms of shape space coverage, which allows the shape redundancy between the different subsets of a given compound collection to be analyzed in a quantitative way. The shape space coverage has been found to originate mainly from the nature and the 3D-geometry (but not the size) of the central scaffold, while the number and nature of the peripheral substituents and conformational aspects were shown to be of minor importance. Substantial shape space coverage has been correlated with broad biological activity by applying the same shape analysis to collections of known bioactive compounds, such as MDDR and the GOLD-set. The aggregate of our results corroborates the intuitive notion that molecular shape is intimately linked to biological activity and that a high degree of shape (hence scaffold) diversity in screening collections will increase the odds of addressing a broad range of biological targets.

Computers in chemistryComputers in chemistry V 0380 Molecular Shape Diversity of Combinatorial Libraries: A Prerequisite for Broad Bioactivity. -(SAUER, W. H. B.; SCHWARZ*, M. K.; J. Chem. Inf. Comput. Sci. 43 (2003) 3, 987-1003; Serono Pharm. Res. Inst., Dep. Chem., CH-1228 Plan-les-Oates, Genova, Switz.; Eng.) -Lindner 36-184

The SwissBioisostere database (http://www.swissbioisostere.ch) contains information on molecular replacements and their performance in biochemical assays. It is meant to provide researchers in drug discovery projects with ideas for bioisosteric modifications of their current lead molecule, as well as to give interested scientists access to the details on particular molecular replacements. As of August 2012, the database contains 21 293 355 datapoints corresponding to 5 586 462 unique replacements that have been measured in 35 039 assays against 1948 molecular targets representing 30 target classes. The accessible data were created through detection of matched molecular pairs and mining bioactivity data in the ChEMBL database. The SwissBioisostere database is hosted by the Swiss Institute of Bioinformatics and available via a web-based interface.

No abstract

Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, neurodegenerative diseases, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel syndrome). The screening of a compound collection led to the identification of a 2-(benzoylaminomethyl)thiophene sulfonamide (AS004509, compound I) as a potent and selective JNK inhibitor. Chemistry and structure--activity relationship (SAR) studies performed around this novel kinase-inhibiting motif indicated that the left and central parts of the molecule were instrumental to maintaining potency at the enzyme. Accordingly, we investigated the JNK-inhibiting properties of a number of variants of the right-hand moiety of the molecule, which led to the identification of 2-(benzoylaminomethyl)thiophene sulfonamide benzotriazole (AS600292, compound 50a), the first potent and selective JNK inhibitor of this class which demonstrates a protective action against neuronal cell death induced by growth factor and serum deprivation.