Computational studies of the binding modes of CCR1 antagonists

Abstract

The CC chemokine receptor 1 (CCR1) is linked to the pathogenesis of chronic inflammatory diseases and is an attractive target for drug discovery research. On the basis of the high-resolution crystal structure of CXC4 chemokine receptor, 3D structure of the human CCR1 was developed by homology modelling. Nine representative antagonists were applied to binding site study with the rational model through molecular docking. Three hydrophobic sites, especially Phe89, Trp90; Trp99, Tyr113; Tyr114 and Cys183, were identified to be essential for their strong hydrophobic interactions with antagonists. Lys94 and Glu287 have been identified as major contributor to ligand binding by H-bond interaction and salt-bridge interaction, respectively. Two hydrophobic subpockets (Regions A and B) and Glu287 may be crucial binding sites for chemokine receptors, whereas Tyr93 and Lys94 may be crucial binding sites of the subtype selectivity for CCR1. They are important in stabilising CCR1–antagonist complexes. Thus, our studies should provide novel insights into the CCR1–antagonist interactions and guide further drug design and mutagenesis studies.

Keywords:

• chemokine
• CC chemokine receptor 1
• homology modelling
• molecular docking
• binding site

Acknowledgements

We gratefully acknowledge the support from Project of Undergraduate Educational Reform & Capacities in Tianjin University (No. 200904050).

Notes

1. Email: [email protected]

2. Email: [email protected]

Additional information

Notes on contributors

Yuan Liu

1

Binhui Chen

2