Department of Molecular Medicine, University of Padua, via A. Gabelli 63, 35121 Padua, Italy.
Department of Chemistry, University of Pavia, Viale Taramelli 10, 27100 Pavia, Italy.
Molecules. 2018 Jul 27;23(8):1874. doi: 10.3390/molecules23081874.
G-quadruplex (G4) nucleic acid structures have been reported to be involved in several human pathologies, including cancer, neurodegenerative disorders and infectious diseases; however, G4 targeting compounds still need implementation in terms of drug-like properties and selectivity in order to reach the clinical use. So far, G4 ligands have been mainly identified through high-throughput screening methods or design of molecules with pre-set features. Here, we describe the development of new heterocyclic ligands through a fragment-based drug discovery (FBDD) approach. The ligands were designed against the major G4 present in the long terminal repeat (LTR) promoter region of the human immunodeficiency virus-1 (HIV-1), the stabilization of which has been shown to suppress viral gene expression and replication. Our method is based on the generation of molecular fragment small libraries, screened against the target to further elaborate them into lead compounds. We screened 150 small molecules, composed by structurally and chemically different fragments, selected from commercially available and in-house compounds; synthetic elaboration yielded several G4 ligands and two final G4 binders, both embedding an amidoxime moiety; one of these two compounds showed preferential binding for the HIV-1 LTR G4. This work presents the discovery of a novel potential pharmacophore and highlights the possibility to apply a fragment-based approach to develop G4 ligands with unexpected chemical features.
G-四链体（G4）核酸结构已被报道参与多种人类疾病，包括癌症、神经退行性疾病和传染病；然而，G4 靶向化合物仍需要在药物样性质和选择性方面进行实施，以达到临床应用。到目前为止，G4 配体主要通过高通量筛选方法或设计具有预设特征的分子来鉴定。在这里，我们通过基于片段的药物发现（FBDD）方法描述了新型杂环配体的开发。这些配体是针对人类免疫缺陷病毒 1（HIV-1）长末端重复（LTR）启动子区域中存在的主要 G4 设计的，其稳定化已被证明可抑制病毒基因表达和复制。我们的方法基于生成分子片段小分子文库，针对目标进行筛选，进一步将其细化为先导化合物。我们筛选了 150 种小分子，由结构和化学上不同的片段组成，这些片段选自市售和内部化合物；通过合成精心设计得到了几种 G4 配体和两个最终的 G4 结合物，两者都嵌入了酰胺肟部分；其中一种化合物显示出对 HIV-1 LTR G4 的优先结合。这项工作揭示了一种新型潜在药效团的发现，并强调了应用基于片段的方法开发具有意外化学特征的 G4 配体的可能性。
