Fig. 3). The second and central ABT-888 chemical structure step (green borders) consists in the identification of the compound’s potential binding mode(s)

by simulating its 3D interaction with the protein (pharmacophore-based pre-alignment: software Alignator/Dolina: Smieško, 2013; full Monte-Carlo sampling: software Cheetah: Rossato et al., 2010 and Vedani et al., 2012). The last step (red borders) comprises the quantification of the individual binding affinities (software BzScore4D) and the estimation of the toxic potential therefrom ( Vedani et al., 2012). These pieces of information—along with the 3D structures of all protein–ligand complexes—are then made available to the client via the user interface. All relevant data can be downloaded and stored locally and, most important, removed completely from the server. The VirtualToxLab servers (currently featuring 512 cores) are hosted by the University of Basel and located in a physically and electronically safe environment. The flexible-docking protocol employed in Alignator and Cheetah aims at identifying all potential binding modes at the target protein, thereby specifically allowing for induced fit and dynamic solvation ( Vedani et al., 2012). ABT-263 The

underlying force field features directional terms for hydrogen Idelalisib bonds and metal–ligand interactions, allows for metal–ligand charge transfer and includes polarization terms

(cf. Fig. 2; Vedani and Huhta, 1990 and Rossato et al., 2010). During the conformational sampling of a small molecule in the binding pocket of a protein, a total of 6000 (optionally: 12,000 in double-sampling mode) different binding poses are generated at each of the 16 currently employed proteins, 120 (240) thereof fully minimized and 12 (24) each are retained for the quantification of the binding energy ( Vedani et al., 2012). This protocol is computationally demanding and results in 20–80 h of CPU time for the estimation of the toxic potential of a single compound. Our Linux cluster currently hosts 512 cores, allowing for an average process rate of 300–400 compounds per day. The sampling protocol has been previously described (Rossato et al., 2010 and Vedani et al., 2012). The calculation of the associated binding affinity, however, has been completely redesigned. While the previously employed mQSAR technology (the 6D-QSAR software Quasar, cf. Vedani et al., 2000, Vedani et al., 2005 and Vedani and Dobler, 2002) represents the highest QSAR level, its predictive power is—as in principle for any such approach—limited to compounds at least similar to the ensemble of ligands represented in the underlying training set.