Similarity Mapplet: Interactive Visualization of the Directory of Useful Decoys and ChEMBL in High Dimensional Chemical Spaces

An Internet portal accessible at www.gdb.unibe.ch has been set up to automatically generate color-coded similarity maps of the ChEMBL database in relation to up to two sets of active compounds taken from the enhanced Directory of Useful Decoys (eDUD), a random set of molecules, or up to two sets of user-defined reference molecules. These maps visualize the relationships between the selected compounds and ChEMBL in six different high dimensional chemical spaces, namely MQN (42-D molecular quantum numbers), SMIfp (34-D SMILES fingerprint), APfp (20-D shape fingerprint), Xfp (55-D pharmacophore fingerprint), Sfp (1024-bit substructure fingerprint), and ECfp4 (1024-bit extended connectivity fingerprint). The maps are supplied in form of Java based desktop applications called “similarity mapplets” allowing interactive content browsing and linked to a “Multifingerprint Browser for ChEMBL” (also accessible directly at www.gdb.unibe.ch) to perform nearest neighbor searches. One can obtain six similarity mapplets of ChEMBL relative to random reference compounds, 606 similarity mapplets relative to single eDUD active sets, 30 300 similarity mapplets relative to pairs of eDUD active sets, and any number of similarity mapplets relative to user-defined reference sets to help visualize the structural diversity of compound series in drug optimization projects and their relationship to other known bioactive compounds.

Fic domain-catalyzed adenylylation: insight provided by the structural analysis of the type IV secretion system effector BepA

Numerous bacterial pathogens subvert cellular functions of eukaryotic host cells by the injection of effector proteins via dedicated secretion systems. The type IV secretion system (T4SS) effector protein BepA from Bartonella henselae is composed of an N-terminal Fic domain and a C-terminal Bartonella intracellular delivery domain, the latter being responsible for T4SS-mediated translocation into host cells. A proteolysis resistant fragment (residues 10-302) that includes the Fic domain shows autoadenylylation activity and adenylyl transfer onto Hela cell extract proteins as demonstrated by autoradiography on incubation with α-[(32)P]-ATP. Its crystal structure, determined to 2.9-Å resolution by the SeMet-SAD method, exhibits the canonical Fic fold including the HPFxxGNGRxxR signature motif with several elaborations in loop regions and an additional β-rich domain at the C-terminus. On crystal soaking with ATP/Mg(2+), additional electron density indicated the presence of a PP(i) /Mg(2+) moiety, the side product of the adenylylation reaction, in the anion binding nest of the signature motif. On the basis of this information and that of the recent structure of IbpA(Fic2) in complex with the eukaryotic target protein Cdc42, we present a detailed model for the ternary complex of Fic with the two substrates, ATP/Mg(2+) and target tyrosine. The model is consistent with an in-line nucleophilic attack of the deprotonated side-chain hydroxyl group onto the α-phosphorus of the nucleotide to accomplish AMP transfer. Furthermore, a general, sequence-independent mechanism of target positioning through antiparallel β-strand interactions between enzyme and target is suggested.