CcpNmr AnalysisScreen, a new software programme with dedicated automated analysis tools for fragment-based drug discovery by NMR

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.

Fragment-to-Lead Medicinal Chemistry Publications in 2020

“…Although not reflected in the table, a prominent feature of the collected 2020 literature involves the further development of fragment-screening technologies. Several studies describe new and improved NMR screening protocols, particularly those to increase throughput by automated analyses of FBDD data, e.g., using freely available software tools such as CcpNmr; or a new automated tool called CSP Analyzer, which uses machine-learning-driven analysis to assess multiple 2D HSQC spectra .…”

Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?

“…Furthermore, from the case studies it appeared that the full analytical power of 1D NMR spectroscopy was often not exploited. Instead, the NMR data appear to be used solely as a binary result, probably also due to a lack of proper computational-and data-analysis tools available at the time the research was conducted (Mureddu et al, 2020). The data obtained from Water-LOGSY and STD experiments offer further quantitative information (Meyer et al, 2004;Cala and Krimm, 2015).…”

“…NMR has often been associated with a requirement for daunting and time-consuming data analysis. There may be a multitude of other undescribed factors, but NMR's lack of modern, more practical, quicker, and unbiased methods, alongside with automated data analysis routines has comparatively slowed the entire NMR-FBDD process, prompting a need for improvements in all these aspects (Mureddu et al, 2020). To this end, we have recently developed a versatile and flexible data-analysis program called AnalysisScreen (Mureddu et al, 2020), part of the CcpNmr Analysis package (Skinner et al, 2016), which presents dedicated provision and capabilities for the analysis of all forms of NMR data used in the NMR-FBDD process, including an integrated CSP analysis (Mureddu and Vuister, 2019).…”

Accelerating BRPF1b hit identification with BioPhysical and Active Learning Screening (BioPALS)

“…Ligand observed NMR : Samples were prepared from a 260 mM protein stock solution in NMR buffer (20 mM NaPi pH 7.5, 150 mM NaCl) and nominally 20 mM compound stock solutions in DMSO‐d 6 (Cambridge Isotope Laboratories) to produce final concentrations of 26 μM protein and 200 μM or 400 μM compound diluted in NMR buffer with 5 % (v/v) D2O, 0.00025 % (w/v) TSP. To limit protein consumption, some compounds were screened in pairs with design of the mixtures aided by the AnalysisScreen [59] from the CCP NMR software suite [60] . Spectra were recorded at 599.73 MHz on a Bruker AVANCE IIIHD spectrometer equipped with a 5 mm TCI cryoprobe.…”