Abstract
Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.
Original language | English |
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Pages (from-to) | 631-649 |
Number of pages | 19 |
Journal | European Journal of Medicinal Chemistry |
Volume | 162 |
Early online date | 30 Oct 2018 |
DOIs | |
Publication status | Published - 15 Jan 2019 |
Keywords
- 3D-QSAR
- Antagonists
- CXCR4 chemokine receptor
- G protein-coupled receptors
- Structure-activity relationship
- Structure-based fragment virtual screening