期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 85, 期 2, 页码 119-136出版社
WILEY
DOI: 10.1111/cbdd.12377
关键词
AMD11070; anti-HIV-1 inhibitors; critical residues; crystal structure; CXCR4; DOCK; H-bond distance; hologram quantitative structure activity relationship; MD; RMSD
资金
- National Basic Research Program of China (973 Program) [2012CB932400]
- National Natural Science Foundation of China [91233115, 21273158, 91227201]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Fund for Innovative Research Teams of Jiangsu Higher Education Institutions
CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane and is implicated in cancer metastasis and inflammation. In the current work, we study the relationship of structure and activity of AMD11070 derivatives and other inhibitors of CXCR4 using HQSAR, docking and molecular dynamics (MD) simulations. We obtain an HQSAR model (q(2)=0.779), and the HQSAR result illustrates that AMD11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD3100, and AMD3465 with CXCR4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD11070 contributes to its high antiretroviral activity. Without a butyl amine moiety, (2,7a-Dihydro-1H-benzoimidazol-2-ylmethyl)-methyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (compound 5a) shows low antiretroviral activity. Our results provide structural details about the interactions between the inhibitors and CXCR4, which are useful for rational drug design of CXCR4.
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