Introducing the CSP Analyzer: A novel Machine Learning-based application for automated analysis of two-dimensional NMR spectra in NMR fragment-based screening.

NMR-based screening, especially fragment-based drug discovery is a valuable approach in early-stage drug discovery. Monitoring fragment-binding in protein-detected 2D NMR experiments requires analysis of hundreds of spectra to detect chemical shift perturbations (CSPs) in the presence of ligands screened. Computational tools are available that simplify the tracking of CSPs in 2D NMR spectra. However, to the best of our knowledge, an efficient automated tool for the assessment and binning of multiple spectra for ligand binding has not yet been described. We present a novel and fast approach for analysis of multiple 2D HSQC spectra based on machine-learning-driven statistical discrimination. The CSP Analyzer features a C# frontend interfaced to a Python ML classifier. The software allows rapid evaluation of 2D screening data from large number of spectra, reducing user-introduced bias in the evaluation. The CSP Analyzer software package is available on GitHub https://github.com/rubbs14/CSP-Analyzer/releases/tag/v1.0 under the GPL license 3.0 and is free to use for academic and commercial uses.

Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.

The parasitic protists of the Trypanosoma genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill Trypanosoma by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the Trypanosoma suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.