6AKY

The Crystal structure of Human Chemokine Receptor CCR5 in complex with compound 34

Summary for 6AKY

• Entry DOI: 10.2210/pdb6aky/pdb
• Descriptor: C-C chemokine receptor type 5,Rubredoxin,C-C chemokine receptor type 5, ZINC ION, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (4 entities in total)
• Functional Keywords: g protein-coupled receptor chemokine receptor ccr5 antagonist complex structure, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 44817.87

Authors

Zhu, Y.,Zhao, Q.,Wu, B. (deposition date: 2018-09-04, release date: 2018-10-24, Last modification date: 2024-10-23)

Primary citation

Peng, P.,Chen, H.,Zhu, Y.,Wang, Z.,Li, J.,Luo, R.H.,Wang, J.,Chen, L.,Yang, L.M.,Jiang, H.,Xie, X.,Wu, B.,Zheng, Y.T.,Liu, H.
Structure-Based Design of 1-Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists.
J. Med. Chem., 61:9621-9636, 2018

PubMed Abstract: CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5-antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 Å resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 μM, which overcomes the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.

PubMed: 30234300
DOI: 10.1021/acs.jmedchem.8b01077

Experimental method

X-RAY DIFFRACTION (2.8 Å)