Ligand 1 H NMR Chemical Shifts as Accurate Reporters for Protein-Ligand Binding Interfaces in Solution.

Autor: Platzer G; Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030-, Vienna, Austria.; MAG-LAB GmbH, Karl-Farkas-Gasse 22, 1030-, Vienna, Austria., Ptaszek AL; Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030-, Vienna, Austria.; Laboratory for Computer-Aided Molecular Design, Division of Medicinal Chemistry, Otto Loewi Research Center, Medical University Graz, Neue Stiftingtalstrasse 6/III, 8010-, Graz, Austria., Böttcher J; Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer Gasse 5-11, 1121-, Vienna, Austria., Fuchs JE; Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer Gasse 5-11, 1121-, Vienna, Austria., Geist L; Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer Gasse 5-11, 1121-, Vienna, Austria., Braun D; Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030-, Vienna, Austria., McConnell DB; Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer Gasse 5-11, 1121-, Vienna, Austria., Konrat R; Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030-, Vienna, Austria., Sánchez-Murcia PA; Laboratory for Computer-Aided Molecular Design, Division of Medicinal Chemistry, Otto Loewi Research Center, Medical University Graz, Neue Stiftingtalstrasse 6/III, 8010-, Graz, Austria., Mayer M; Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer Gasse 5-11, 1121-, Vienna, Austria.
Jazyk: angličtina
Zdroj: Chemphyschem : a European journal of chemical physics and physical chemistry [Chemphyschem] 2024 Jan 02; Vol. 25 (1), pp. e202300636. Date of Electronic Publication: 2023 Nov 13.
DOI: 10.1002/cphc.202300636
Abstrakt: The availability of high-resolution 3D structural information is crucial for investigating guest-host systems across a wide range of fields. In the context of drug discovery, the information is routinely used to establish and validate structure-activity relationships, grow initial hits from screening campaigns, and to guide molecular docking. For the generation of protein-ligand complex structural information, X-ray crystallography is the experimental method of choice, however, with limited information on protein flexibility. An experimentally verified structural model of the binding interface in the native solution-state would support medicinal chemists in their molecular design decisions. Here we demonstrate that protein-bound ligand 1 H NMR chemical shifts are highly sensitive and accurate probes for the immediate chemical environment of protein-ligand interfaces. By comparing the experimental ligand 1 H chemical shift values with those computed from the X-ray structure using quantum mechanics methodology, we identify significant disagreements for parts of the ligand between the two experimental techniques. We show that quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) ensembles can be used to refine initial X-ray co-crystal structures resulting in a better agreement with experimental 1 H ligand chemical shift values. Overall, our findings highlight the usefulness of ligand 1 H NMR chemical shift information in combination with a QM/MM MD workflow for generating protein-ligand ensembles that accurately reproduce solution structural data.
(© 2023 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: