Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India.
Med Chem. 2011 Jul;7(4):301-8. doi: 10.2174/157340611796150932.
Trans activation response (TAR) region is an RNA target of considerable importance in controlling the replication cycle of the human immunodeficiency virus (HIV). At a transcriptional level, HIV-1 is regulated by means of the interaction between Tat protein and TAR RNA. The TAR-Tat complex is an attractive target for developing novel antiviral drugs. Herein, the recognition modes of 8 structurally different ligands, as mimics of Tat protein, in complex with a TAR RNA are investigated using the DOCK 6.4 flexible docking protocol in association with the newly-implemented scoring function AMBER including solvation implicitly through the generalized Born solvent-accessible surface area (GB/SA) continuum model. The TAR RNA-ligand interactions are further characterized and contrasted using the nature of separate contributions to the stability of the complexes. Several interesting implications for the key challenge, the development of low molecular weight ligands binding to HIV-1 TAR RNA with high affinity and specificity, are discussed.
反式激活反应（TAR）区域是控制人类免疫缺陷病毒（HIV）复制周期的重要 RNA 靶标。在转录水平上，HIV-1 的调控是通过 Tat 蛋白与 TAR RNA 的相互作用实现的。TAR-Tat 复合物是开发新型抗病毒药物的有吸引力的靶标。在此，使用 DOCK 6.4 柔性对接协议以及新实现的 AMBER 评分函数（通过广义 Born 溶剂可及表面积（GB/SA）连续体模型隐式包含溶剂化作用），研究了 8 种结构不同的配体（作为 Tat 蛋白的模拟物）与 TAR RNA 形成复合物的识别模式。进一步使用对复合物稳定性的单独贡献的性质来表征和对比 TAR RNA-配体相互作用。讨论了针对关键挑战的几个有趣的启示，即开发与 HIV-1 TAR RNA 具有高亲和力和特异性的低分子量配体。
