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Ranking Hits From Saturation Transfer Difference Nuclear Magnetic Resonance-Based Fragment Screening.

ABSTRACT: Fragment-based screening is an established route to identify low-molecular-weight molecules to generate high-affinity inhibitors in drug discovery. The affinities of these early hits from fragment screenings require a highly sensitive biophysical screening technique. Saturation transfer difference (STD) nuclear magnetic resonance (NMR) is one of the most popular methods owing to its high sensitivity for low-affinity ligands. It would be highly beneficial if rank-ordering of hits according to their affinity from an initial or counter-screen could be performed-a selection criterion found in the literature. We applied Complete Relaxation and Conformational Exchange Matrix (CORCEMA) theory adapted for saturation transfer (ST) measurements (CORCEMA-ST) calculations to predict STD NMR results from a large set of fragment/receptor pairs to investigate the boundaries under which the assumption holds true that a high STD effect can be applied to select for higher-affinity fragments. Overall, we come to the conclusion that this assumption is invalid.

SUBMITTER: Aretz J

PROVIDER: S-EPMC6473174 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Ranking Hits From Saturation Transfer Difference Nuclear Magnetic Resonance-Based Fragment Screening.

Aretz Jonas J Rademacher Christoph C

Frontiers in chemistry 20190412

Fragment-based screening is an established route to identify low-molecular-weight molecules to generate high-affinity inhibitors in drug discovery. The affinities of these early hits from fragment screenings require a highly sensitive biophysical screening technique. Saturation transfer difference (STD) nuclear magnetic resonance (NMR) is one of the most popular methods owing to its high sensitivity for low-affinity ligands. It would be highly beneficial if rank-ordering of hits according to the ...[more]

PMID: 31032246

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Project description:ObjectivesThe main function of influenza neuraminidase (NA) involves enzymatic cleavage of sialic acid from the surface of host cells resulting in the release of the newly produced virions from infected cells, as well as aiding the movement of virions through sialylated mucus present in the respiratory tract. However, there has previously been little information on the binding affinity of different forms of sialylated glycan with NA. Our objectives were then to investigate both sialic acid binding and cleavage of neuraminidase at an atomic resolution level.DesignNuclear magnetic resonance (NMR) spectroscopy was used to investigate pH and temperature effects on binding and cleavage as well as to interrogate the selectivity of human-like or avian-like receptors for influenza neuraminidase N1 derived from a range of different influenza virus strains including human seasonal H1N1, H1N1pdm09 and avian H5N1.ResultsWe demonstrated that an acidic pH and physiological temperature are required for efficient NA enzymatic activity; however a change in the pH had a minimum effect on the NA-sialic acid binding affinity. Our data comparing ?-2,3- and ?-2,6-sialyllactose indicated that the variation in neuraminidase activity on different ligands correlated with a change in binding affinity. Epitope mapping of the sialylglycans interacting with NAs from different viral origin showed different binding profiles suggesting that different binding conformations were adopted.ConclusionsThe data presented in this study demonstrated that physicochemical conditions (pH in particular) could affect the NA enzymatic activity with minor effect on ligand binding. NA cleavage specificity seemed to be associated with a difference in binding affinity to different ligands, suggesting a relationship between the two events. These findings have implications regarding the replication cycle of influenza infection in the host where different sialidase activities would influence penetration through the respiratory mucin barrier and the release of the newly generated virus from the infected cells.

Dataset Information

Ranking Hits From Saturation Transfer Difference Nuclear Magnetic Resonance-Based Fragment Screening.

Publications

Ranking Hits From Saturation Transfer Difference Nuclear Magnetic Resonance-Based Fragment Screening.

Similar Datasets

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