Gisbert Schneider

..The results demonstrate that appropriate data preprocessing is an essential step in solving classification tasks...

..A comparison of molecular descriptors suggests that holographic descriptors might be advantageous over binary fingerprints for ligand-based de novo design...

..The software allows for visualization of the training process, which has been shown to be particularly valuable for teaching purposes...

..In particular, an application of the self-organizing map technique is presented for natural product-derived compound and library design...

..Focus of the review is on machine learning systems, highlighting four concepts: the artificial neural feed-forward network, the self-organizing map (SOM), the Hidden-Markov-Model (HMM), and the support vector machine (SVM)...

..In this review, we outline the various design concepts and highlight current developments in computer-based de novo design...

..The strategy might be particularly useful in projects in which structure-based design cannot be applied because of a lack of receptor structure information, for example, in the many projects aiming at finding new GPCR modulators...

..Results show that both algorithms can be used in the context of virtual screening. Intersecting the result lists obtained with both algorithms improved enrichment factors while losing only few chemotypes...

....

..The new method provides a means for selecting drug targets and potential ligand-binding pockets based on structural considerations and addresses orphan binding sites...

....

..This new pseudoreceptor approach has demonstrated its suitability for both structure-based prioritization of protein receptor models, and ligand-based virtual screening with the aim to perform scaffold hopping...

..Furthermore, pharmacological profiling of toxicity and eicosanoid screening with LC/MS-MS was applied to characterize this new class of mPGES-1 inhibitors...

..Thus, we provide strong evidence that SBE13 leaves checkpoint control in primary cells unaffected making it a remarkable future anti-cancer therapeutic...

..The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets...

..Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening...

..Here, we present a successful virtual screening study that results in a potent nonacidic mPGES-1 inhibitor lacking COX inhibition...

..The human pathogen Helicobacter pylori (H. pylori) is a main cause for gastric inflammation and cancer. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention...

..In 82% of the unbound samples, docking poses were ranked within the top ten solutions with an RMSD < 10 A to the target solution...

..We demonstrate that for one or multiple templates of a given chemotype, other chemotypes are reached during de novo compound generation, thus indicating successful scaffold-hops...

..We already implemented these interfaces for the Chemistry Development Toolkit...

..Pocket frameworks highlight potentially preferred modes of ligand-receptor interactions and will help facilitate the identification of druggable subpockets suitable for ligand affinity and selectivity optimization...

..Evolving compound libraries are particularly suited for hit and lead finding in situations where resources are limited and the complete testing of a large screening compound collection is prohibitive...

..We conclude that this fragment-based design principle is suited as an idea generator for the automated design of novel leadlike molecules...

..These phenomena are theoretically characterized and illustrated on both artificial and real (bioactivity) data...

..We developed a ligand-based computational method for drug-target prediction that is independent from protein structural analysis...

..Recent practical validation studies are presented that have already demonstrated that rule-based fragment assembly can result in novel synthesizable compounds with druglike properties and a desired biological activity...

..Chemical synthesis was straightforward, and bioactivity of the designed molecule was confirmed in a FRET assay. This study demonstrates the practicability of de novo design to generating RNA ligands containing novel molecular scaffolds...

..Here, we review the field of pseudoreceptor modelling techniques along with recent hit and lead finding applications, and critically discuss prerequisites, advantages and limitations of the various approaches...

..Their potential for sequence-based prediction of turn structures is discussed...

..The results demonstrate the potential of natural-product-derived screening libraries for hit and lead structure identification...

..Although a special targeting signal at the N-terminal end of effector proteins has been proposed in literature its exact characteristics remain unknown...

..Finally, we introduce a performance index that helps prioritize canonization approaches without the need for extensive retrospective evaluation...

..A Java implementation of the clustering method is available via the Internet (http://www.modlab.de)...

..We show that there exists an optimal combination of the size of a screening library and the number of iterative screening rounds with the aim to keep experimental efforts at a minimum...

..We evaluated our molecular similarity measure by using it as a kernel in support vector machine classification and regression applied to several pharmaceutical and toxicological data sets, with encouraging results...

..We further demonstrate that a nearest neighbor algorithm can successfully be applied to map from continuous search space to discrete chemical space...

..78. This classifier can be used for fast filtering of compound libraries in virtual screening applications...

..Our olfaction-inspired method was successfully applied to predicting bioactivities of pharmaceutically active compounds with high accuracy. It represents a way to efficiently connect chemical structure with biological activity space...

..We further show that signal peptide cleavage results in a positional alignment of PEXEL from both proteins with, and without, a signal peptide...

..Seventy-one percent correct prediction of GPCR ligands was obtained...

..This concept provides a structural framework for identifying and understanding multiple targeting and post-targeting functions...

..Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed...

..In a validation study, 93 % of the nonblocking agents and 71 % of the hERG channel blockers were correctly classified. This virtual screening method can be used for general compound-library shaping and combinatorial library design...

....

..We assessed the performance of the OPSO method on a set of five artificial fitness functions and compared it to the performance of two popular PSO implementations...

..In conclusion, we show that catG is a functional and pharmacologically relevant target of BAs, and interference with catG could explain some of the anti-inflammatory properties of frankincense...

..This study suggests that Plk1 kinase inhibitors targeting the inactive conformation of Plk1 may be considered for the development of cancer therapeutics...

..This review provides a brief introduction to the basic ideas and outlines computational tools currently used. We also provide several examples of where virtual screening has proved successful, highlighting the usefulness of the approach...

..The experimental results present evidence that the canonical sequence motives of the SYFPEITHI database on their own are insufficient for predicting MHC I protein stabilization...

..The theory of SVM and ANN training is briefly reviewed...

..Appropriately weighted fuzzy pharmacophore models performed better in retrospective screening than similarity searching using only a single query molecule. The new pharmacophore method was shown to complement existing approaches...

..While the Java version selects the same compounds independent of the virtual machine used, the C version produces slightly different subsets depending on the compiler and on the optimization settings...

..It thereby represents a practical solution for compound screening in the early hit and lead finding phase of a drug discovery project...

....

....

..It was demonstrated that the SVM machine-learning method can be used in virtual screening and be analyzed in a human-interpretable way that results in a set of rules for designing novel molecules...

..The suitability of a descriptor critically depends on the ligand-receptor interaction under investigation. For ligand-based similarity searching it is recommended to exploit several descriptors in parallel...

..This filter will be a valuable tool for the prioritization of compounds from large databases, for compound purchase and biological testing, and for building new virtual libraries...

..The hits had molecular scaffolds different from those of the reference molecules...