Abstract
Fragment-based drug discovery or FBDD is one of the main methods used by industry and academia for identifying drug-like candidates in early stages of drug discovery. NMR has a significant impact at any stage of the drug discovery process, from primary identification of small molecules to the elucidation of binding modes for guiding optimisations. The essence of NMR as an analytical tool, however, requires the processing and analysis of relatively large amounts of single data items, e.g. spectra, which can be daunting when managed manually. One bottleneck in FBDD by NMR is a lack of adequate and well-integrated resources for NMR data analysis that are freely available to the community. Thus, scientists typically resort to manually inspecting large datasets and relying predominantly on subjective interpretations. In this manuscript, we present CcpNmr AnalysisScreen, a software package that provides computational tools for automated analysis of FBDD data by NMR. We outline how the quality of collected spectra can be evaluated quickly, and how robust workflows can be optimised for reliable and rapid hit identification. With an intuitive graphical user interface and powerful algorithms, AnalysisScreen enables easy analysis of the large datasets needed in the early process of drug discovery by NMR.
Highlights
Over the years, the versatility of NMR as a non-destructive and adaptable analytical tool has encouraged the development of multiple fragment-based drug discovery (FBDD) approaches by NMR (Dias and Ciulli (2014)
An NMR based FBDD screening experiment requires the handling of a large volume of spectral data and metadata
We included in AnalysisScreen the option to use spreadsheets in Excel format as a data loading mechanism
Summary
The versatility of NMR as a non-destructive and adaptable analytical tool has encouraged the development of multiple fragment-based drug discovery (FBDD) approaches by NMR (Dias and Ciulli (2014) Nowadays, it is possible, albeit not frequently done, to conduct the entire drug discovery process by NMR: from hit detection and binding site identification to the determination of the ligand orientation and hit optimisation. Assuming the target of interest has already been identified, hit identification is usually the first step in the drug discovery process and this is the aspect we concentrate on in this article This can be achieved by NMR using a number of common ligand-detected NMR methods (Dias and Ciulli 2014), namely 1H-relaxation-edited (commonly called 1H), saturation transfer difference (STD) (Mayer and Meyer 1999), WaterLOGSY (Dalvit et al 2000) (Fig. 1a), and alternative relaxation experiments (T1ρ, T2). A number of complementary techniques, i.e. target immobilised NMR screening (TINS) Vanwetswinkel et al (2005), spin label analysis (Jahnke 2002), paramagnetic relaxation enhancement (PRE) (Guan et al 2013) and 19F experiments (Dalvit and Vulpetti 2012) have been successfully used in the primary hit identification process
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