Hologram Quantitative Structure Activity Relationship, Docking, and Molecular Dynamics Studies of Inhibitors for CXCR 4

• Published in: Chemical biology & drug design Vol. 85; no. 2; pp. 119 - 136
• Main Authors: Zhang, Chongqian, Du, Chunmiao, Feng, Zhiwei, Zhu, Jingyu, Li, Youyong
• Format: Journal Article
• Language: English
• Published: 01.02.2015
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12377

CXCR 4 plays a crucial role as a co‐receptor with CCR 5 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 AMD 11070 derivatives and other inhibitors of CXCR 4 using HQSAR , docking and molecular dynamics ( MD ) simulations. We obtain an HQSAR model ( q 2  = 0.779), and the HQSAR result illustrates that AMD 11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD 3100, and AMD 3465 with CXCR 4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD 11070 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 CXCR 4, which are useful for rational drug design of CXCR 4.