Application of 3D Zernike descriptors to shape-based ligand similarity searching

Background: The identification of promising drug leads from a large database of compounds is an important step in the preliminary stages of drug design. Although shape is known to play a key role in the molecular recognition process, its application to virtual screening poses significant hurdles both in terms of the encoding scheme and speed. Results: In this study, we have examined the efficacy of the alignment independent three-dimensional Zernike descriptor (3DZD) for fast shape based similarity searching. Performance of this approach was compared with several other methods including the statistical moments based ultrafast shape recognition scheme (USR) and SIMCOMP, a graph matching algorithm that compares atom environments. Three benchmark datasets are used to thoroughly test the methods in terms of their ability for molecular classification, retrieval rate, and performance under the situation that simulates actual virtual screening tasks over a large pharmaceutical database. The 3DZD performed better than or comparable to the other methods examined, depending on the datasets and evaluation metrics used. Reasons for the success and the failure of the shape based methods for specific cases are investigated. Based on the results for the three datasets, general conclusions are drawn with regard to their efficiency and applicability

Generating modeling data from repeat-dose toxicity reports

Over the past decades, pharmaceutical companies have conducted a large number of high-quality in vivo repeat-dose toxicity (RDT) studies for regulatory purposes. As part of the eTOX project, a high number of these studies have been compiled and integrated into a database. This valuable resource can be queried directly, but it can be further exploited to build predictive models. As the studies were originally conducted to investigate the properties of individual compounds, the experimental conditions across the studies are highly heterogeneous. Consequently, the original data required normalization/standardization, filtering, categorization and integration to make possible any data analysis (such as building predictive models). Additionally, the primary objectives of the RDT studies were to identify toxicological findings, most of which do not directly translate to in vivo endpoints. This article describes a method to extract datasets containing comparable toxicological properties for a series of compounds amenable for building predictive models. The proposed strategy starts with the normalization of the terms used within the original reports. Then, comparable datasets are extracted from the database by applying filters based on the experimental conditions. Finally, carefully selected profiles of toxicological findings are mapped to endpoints of interest, generating QSAR-like tables. In this work, we describe in detail the strategy and tools used for carrying out these transformations and illustrate its application in a data sample extracted from the eTOX database. The suitability of the resulting tables for developing hazard-predicting models was investigated by building proof-of-concept models for in vivo liver endpoints.Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115002 (eTOX), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contributions. Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777365 (eTRANSAFE). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies' in-kind contributions