BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
J Chem Inf Model. 2011 Aug 22;51(8):1986-98. doi: 10.1021/ci200194w. Epub 2011 Jul 26.
The ribonuclease H (RNase H) domain on the p66 monomer of HIV-1 reverse transcriptase enzyme has become a target for inhibition. The active site is one potential binding site, but other RNase H sites can accommodate inhibitors. Using a combination of experimental and computational studies, potential new binding sites and binding modes have been identified. Libraries of compounds were screened with an experimental assay to identify actives without knowledge of the binding site. The compounds were computationally docked at putative binding sites. Based on positive enrichment of natural-product actives relative to the database of compounds, we propose that many inhibitors bind to an alternative, potentially allosteric, site centered on Q507 of p66. For a series of hydrazone compounds, a small amount of positive enrichment was obtained when active compounds were bound by induced-fit docking at the interface between the DNA:RNA substrate and the RNase H domain near residue Q500.
HIV-1 逆转录酶 p66 单体上的核糖核酸酶 H (RNase H) 结构域已成为抑制的靶点。活性位点是一个潜在的结合位点，但其他 RNase H 位点可以容纳抑制剂。通过实验和计算研究的结合，已经确定了潜在的新结合位点和结合模式。使用实验测定法筛选化合物文库，以在不了解结合位点的情况下鉴定活性物质。对化合物进行计算对接，以确定潜在的结合位点。基于天然产物活性物质相对于化合物数据库的正富集，我们提出许多抑制剂结合到一个替代的、潜在的变构位点，该位点以 p66 的 Q507 为中心。对于一系列腙类化合物，当活性化合物通过诱导契合对接结合到位于 Q500 附近的 RNase H 结构域与 DNA:RNA 底物之间的界面时，获得了少量的正富集。
