Blanchet Marc-Frédérick, St-Onge Karine, Lisi Véronique, Robitaille Julie, Hamel Sylvie, Major François
Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada Department of Computer Science and Operations Research, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.
Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.
Nucleic Acids Res. 2014;42(17):11261-71. doi: 10.1093/nar/gku816. Epub 2014 Sep 8.
Anti-infection drugs target vital functions of infectious agents, including their ribosome and other essential non-coding RNAs. One of the reasons infectious agents become resistant to drugs is due to mutations that eliminate drug-binding affinity while maintaining vital elements. Identifying these elements is based on the determination of viable and lethal mutants and associated structures. However, determining the structure of enough mutants at high resolution is not always possible. Here, we introduce a new computational method, MC-3DQSAR, to determine the vital elements of target RNA structure from mutagenesis and available high-resolution data. We applied the method to further characterize the structural determinants of the bacterial 23S ribosomal RNA sarcin-ricin loop (SRL), as well as those of the lead-activated and hammerhead ribozymes. The method was accurate in confirming experimentally determined essential structural elements and predicting the viability of new SRL variants, which were either observed in bacteria or validated in bacterial growth assays. Our results indicate that MC-3DQSAR could be used systematically to evaluate the drug-target potentials of any RNA sites using current high-resolution structural data.
抗感染药物作用于感染因子的关键功能，包括其核糖体和其他重要的非编码RNA。感染因子对药物产生耐药性的原因之一是发生了突变，这些突变在维持关键元件的同时消除了药物结合亲和力。识别这些元件基于对存活和致死突变体及相关结构的测定。然而，并非总是能够以高分辨率确定足够数量突变体的结构。在此，我们引入一种新的计算方法——MC-3DQSAR，以根据诱变和可用的高分辨率数据确定靶标RNA结构的关键元件。我们应用该方法进一步表征细菌23S核糖体RNA的帚曲霉素-蓖麻毒素环（SRL）以及铅激活和锤头状核酶的结构决定因素。该方法在确认实验确定的必需结构元件以及预测新SRL变体的存活能力方面是准确的，这些新变体要么在细菌中观察到，要么在细菌生长试验中得到验证。我们的结果表明，MC-3DQSAR可利用当前的高分辨率结构数据系统地评估任何RNA位点的药物靶标潜力。
