鉴定人类免疫缺陷病毒1型包装信号Ψ的茎环3核糖核酸的特异性小分子配体。

Identification of specific small molecule ligands for stem loop 3 ribonucleic acid of the packaging signal Psi of human immunodeficiency virus-1.

作者信息

Warui Douglas M, Baranger Anne M

机构信息

Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA.

出版信息

J Med Chem. 2009 Sep 10;52(17):5462-73. doi: 10.1021/jm900599v.

DOI:10.1021/jm900599v

PMID:19691339

Abstract

We have screened the NCI diversity set library for molecules that bind specifically to stem loop 3 (SL3) RNA of the packaging element Psi of HIV-1 using the docking programs DOCK and AutoDock, followed by MD simulations. The association of the predicted ligands with SL3 RNA was characterized using fluorescence, ITC, UV-melting, CD, and footprinting techniques. Nine ligands for SL3 RNA have been identified, four of which bind with higher affinity to SL3 RNA than to either single- or double-stranded RNA motifs. The most selective ligands, 9 (NSC252359) and 5 (NSC123111), bind SL3 RNA with dissociation constants of 11 microM and 98 microM, respectively. Compound 9 binds with 4-7-fold higher affinity to SL3 RNA than to the other tetraloops found in Psi-RNA, SL2 and SL4 RNAs. The results suggest that both 9 and 5 bind to the stem region of SL3 RNA without large distortions of the SL3 RNA.

摘要

我们使用对接程序DOCK和AutoDock，随后进行分子动力学（MD）模拟，在NCI多样性集文库中筛选了能特异性结合HIV-1包装元件ψ的茎环3（SL3）RNA的分子。利用荧光、等温滴定量热法（ITC）、紫外熔解、圆二色性（CD）和足迹技术对预测配体与SL3 RNA的结合进行了表征。已鉴定出9种SL3 RNA的配体，其中4种与SL3 RNA的结合亲和力高于单链或双链RNA基序。最具选择性的配体9（NSC252359）和5（NSC123111）与SL3 RNA的解离常数分别为11微摩尔和98微摩尔。化合物9与SL3 RNA的结合亲和力比在ψ-RNA中发现的其他四环（SL2和SL4 RNA）高4至7倍。结果表明，9和5均与SL3 RNA的茎区结合，且不会使SL3 RNA发生大的变形。