Taylor Cooper A, Miller Bill R, Parish Carol A
Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, 28 Westhampton Way, Richmond, VA 23173, United States.
Department of Chemistry, Truman State University, 100 E. Normal Ave, Kirksville, MO 63501, United States.
J Mol Graph Model. 2017 Aug;75:71-79. doi: 10.1016/j.jmgm.2017.02.012. Epub 2017 Feb 24.
The human immunodeficiency virus (HIV) infects healthy human cells by binding to the glycoprotein cluster of differentiation 4 receptors on the surface of helper T-cells, along with either of two chemokine receptors, CC chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). Recently, a pyrazolo-piperdine ligand was synthesized and the corresponding biological data showed good binding to both chemokine receptors, effectively blocking HIV-1 entry. Here, we exhaustively assess the atomistic binding interactions of this compound with both CCR5 and CXCR4, and we find that binding is driven by π-stacking interactions between aromatic rings on the ligand and receptor residues, as well as electrostatic interactions involving the protonated piperidine nitrogen. However, these favorable binding interactions were partially offset by unfavorable desolvation of active site glutamates and aspartates, prompting our proposal of a new, synthetically-accessible derivative designed to increase the electrostatic interactions without compromising the π-stacking features.
人类免疫缺陷病毒（HIV）通过与辅助性T细胞表面的分化簇4糖蛋白受体结合，以及与两种趋化因子受体之一——C-C趋化因子受体5型（CCR5）或C-X-C趋化因子受体4型（CXCR4）结合，感染健康的人体细胞。最近，合成了一种吡唑并哌啶配体，相应的生物学数据表明它与两种趋化因子受体都具有良好的结合能力，能有效阻断HIV-1的进入。在此，我们详尽地评估了该化合物与CCR5和CXCR4的原子级结合相互作用，发现结合是由配体上的芳香环与受体残基之间的π-堆积相互作用以及涉及质子化哌啶氮的静电相互作用驱动的。然而，这些有利的结合相互作用被活性位点谷氨酸和天冬氨酸的不利去溶剂化部分抵消，促使我们提出一种新的、可通过合成获得的衍生物，旨在在不损害π-堆积特征的情况下增强静电相互作用。
