Namanja AT, Xu J, Wu H et al (2019) NMR-based fragment screening and lead discovery accelerated by principal component analysis. Molecules 25:4597įielding L (2003) NMR methods for the determination of protein-ligand dissociation constants. ChemBioChem 19:448–458Įmwas AH, Szczepski K, Poulson BG et al (2020) NMR as a “gold standard” method in drug design and discovery. Magn Reson Chem 53:558–264Įgner JM, Jensen DR, Olp MD et al (2018) Development and validation of 2D difference intensity analysis for chemical library screening by protein-detected NMR spectroscopy. Anal Chem 89:11839–11845Ĭobas C, Iglesias I, Seoane F (2015) NMR data visualization, processing, and analysis on mobile devices. J Pharm Sci 102:1724–1733Īrbogast LW, Delaglio F, Schiel JE, Marino JP (2017) Multivariate analysis of two-dimensional 1H, 13C methyl NMR spectra of monoclonal antibody therapeutics to facilitate assessment of higher order structure. J Am Chem Soc 131:3448–3449Īmezcua CA, Szabo CM (2013) Assessment of higher order tructure comparability in therapeutic proteins using nuclear magnetic resonance spectroscopy. Graphical abstractĪmero C, Schanda P, Asunción Durá M et al (2009) Fast two-dimensional NMR spectroscopy of high molecular weight protein assemblies. The accuracy and speed of the tools are demonstrated on 2D NMR binding data collected on ligands used in the development of potential inhibitors of the anti-apoptotic MCL-1 protein. Toward this end, we implemented and evaluated a set of algorithms for automated peak tracing, spectral binning, and variance analysis by PCA, and a new tool for spectral data intensity comparison using ECHOS. The package covers three main tasks: (1) unsupervised profiling of raw data to identify outlier data points to exclude in subsequent analyses (2) batch processing of single-point spectra to identify and rank binders based on chemical shift perturbations or spectral peak intensity changes and (3) batch processing of multiple titration series to derive binding affinities ( K D) by tracing the changes in peak locations or measuring global spectral changes. We hereby present the development of a set of software tools within the MestReNova (Mnova) package for analyzing 2D NMR for FBDD and hit validation purposes. Unlike the more frequently used ligand-observed 1D NMR techniques, protein-observed 2D 1H- 15N or 1H- 13C heteronuclear correlation (HSQC or HMQC) methods offer insights that include the mechanism of ligand engagement on the target and direct binding affinity measurements in addition to routine screening. Starting from a library of small compounds, ligand- or protein-observed NMR methods are employed to detect binders, typically weak, that become the starting points for structure–activity relationships (SAR) by NMR. On Line Database of Ensemble Representatives And DOmains (OLDERADO) provides analysis of clustering and domain composition for NMR structure ensembles.Fragment-based drug discovery (FBDD) and validation of small molecule binders using NMR spectroscopy is an established and widely used method in the early stages of drug discovery. The whole ensemble is deposited in the PDB. The outcome of MD simulation is an ensemble of structures (usually 10-20) which, when combined, best satisfy the experimental data. These short distances constitute constraints for molecular dynamics (MD) simulation software, which attempt to satisfy as many of them as possible. The measurements in NMR spectroscopy are a number of different complex spectra that report, among other things, on the chemical environment for the magnetically active nuclei (most commonly 1H, 13C and 15N), on chemical bond connections between nuclei, and on short distances between specific atoms. Typical data collection may take 2-3 weeks for a small soluble protein, but can be substantially longer for larger systems. It utilises the fact that some atomic nuclei are magnetically active and can emit radio frequency signals when placed in a strong external magnetic field (on the order of 10-20 Tesla, which is almost a million times stronger than the Earth’s magnetic field on the surface). Nuclear magnetic resonance (NMR) spectroscopy (for the time being) is the second most common method of structure determination, providing ~7% of all entries in the PDB.
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