Journal
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
Volume 9, Issue 12, Pages 3361-3367Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.8b01443
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Funding
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08030302, XDA12020355]
- Ministry of Science and Technology of China [2016YEA0500700, 2014CB910600]
- National Natural Science Foundation of China [U1632153, 21703254]
- Singapore Ministry of Education Academic Research Fund Tier 2 [MOE2017-T2-1-125]
- Fundamental Research Funds for the Central Universities [WK2070080002, WK2060190086]
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Delineation of protein ligand interaction modes is key for rational drug discovery. The availability of complex crystal structures is often limited by the aqueous solubility of the compounds, while lead-like compounds with micromolar affinities normally fall into the NMR intermediate exchange regime, in which severe line broadening to beyond the detection of interfacial resonances limits NMR applications. Here, we developed a new method to retrieve low populated bound-state H-1 pseudocontact shifts (PCSs) using paramagnetic relaxation dispersion (RD). We evaluated using a H-1 PCS-RD approach in a BRM bromodomain lead-like inhibitor to filter molecular docking poses using multiple intermolecular structural restraints. Considering the universal presence of proton atoms in druglike compounds, our work will have wide application in structure guided drug discovery even under an extreme condition of NMR intermediate exchange and low aqueous solubility of ligands.
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