title: Hologram quantitative structure activity relationship, docking, and molecular dynamics studies of inhibitors for CXCR4.
abstract: 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.
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, China.
authors.forename: Chongqian
authors.initials: C
authors.lastname: Zhang
authors.forename: Chunmiao
authors.initials: C
authors.lastname: Du
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Feng
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhu
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles; D002082:Butylamines; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000494:pharmacology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D019380:Anti-HIV Agents; D001562:Benzimidazoles; D002082:Butylamines; D006573:Heterocyclic Compounds, 1-Ring; D019718:Receptors, CXCR4; C494414:mavorixafor
keywords: AMD11070; CXCR4; DOCK; H-bond distance; MD; RMSD; anti-HIV-1 inhibitors; critical residues; crystal structure; hologram quantitative structure activity relationship