A Benchmark Study of Protein–Fragment Complex Structure Calculations with NMR2
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Date
2023-09-02
Publication Type
Journal Article
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yes
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Abstract
Protein-fragment complex structures are particularly sought after in medicinal chemistry to rationally design lead molecules. These structures are usually derived using X-ray crystallography, but the failure rate is non-neglectable. NMR is a possible alternative for the calculation of weakly interacting complexes. Nevertheless, the time-consuming protein signal assignment step remains a barrier to its routine application. NMR Molecular Replacement (NMR2) is a versatile and rapid method that enables the elucidation of a protein-ligand complex structure. It has been successfully applied to peptides, drug-like molecules, and more recently to fragments. Due to the small size of the fragments, ca < 300 Da, solving the structures of the protein-fragment complexes is particularly challenging. Here, we present the expected performances of NMR2 when applied to protein-fragment complexes. The NMR2 approach has been benchmarked with the SERAPhic fragment library to identify the technical challenges in protein-fragment NMR structure calculation. A straightforward strategy is proposed to increase the method's success rate further. The presented work confirms that NMR2 is an alternative method to X-ray crystallography for solving protein-fragment complex structures.
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published
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Journal / series
Volume
24 (18)
Pages / Article No.
14329
Publisher
MDPI
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Subject
NMR2; NMR spectroscopy; drug design; complex structure; fragment; FBDD; structure-activity relationship
Organisational unit
03782 - Riek, Roland / Riek, Roland