Docking to RNA via root-mean-square-deviation-driven energy minimization with flexible ligands and flexible targets
Docking to RNA via root-mean-square-deviation-driven energy minimization with flexible ligands and flexible targets
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DOI：
10.1021/ci8000327
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发表时间：
2008-06-01
影响因子：
5.6
通讯作者：
James, Thomas L.
中科院分区：
文献类型：
--
作者：
Guilbert, Christophe;James, Thomas L.
基于结构的药物设计作为开发新药这一漫长过程中的关键第一步，目前在蛋白质方面已经相当成熟。在很多方面，RNA可能是比蛋白质更好的疾病治疗靶点，因为它在翻译途径的上游，所以抑制单个mRNA分子可以阻止数千种蛋白质基因产物的产生。虚拟筛选通常是基于结构的药物设计的起点。然而，由于RNA具有更高的内在柔性和高度带电的结构，小分子与RNA的计算对接似乎比与蛋白质的对接更具挑战性。先前对RNA对接的尝试表明需要一种新的方法。我们在此提出一种利用分子模拟技术的新算法，以兼顾核酸和配体的柔性。在这种方法中，允许配体和受体都有一定的柔性，它们可以通过诱导契合相互结合，因为柔性配体探测受体表面。一个可能的配体可以通过在均方根距离约束下进行能量最小化来探索受体表面的低能路径。我们的方法在57个RNA复合物（33个晶体结构和24个NMR结构）上进行了测试；这是迄今为止重现实验性RNA结合构象的最大数据集。通过我们的方法，对于74%的测试复合物，最低能量构象在2.5埃的原子均方根偏差内重现了实验性结合构象。
Structure-based drug design is now well-established for proteins as a key first step in the lengthy process of developing new drugs. In many ways, RNA may be a better target to treat disease than a protein because it is upstream in the translation pathway, so inhibiting a single mRNA molecule could prevent the production of thousands of protein gene products. Virtual screening is often the starting point for structure-based drug design. However, computational docking of a small molecule to RNA seems to be more challenging than that to protein due to the higher intrinsic flexibility and highly charged structure of RNA. Previous attempts at docking to RNA showed the need for a new approach. We present here a novel algorithm using molecular simulation techniques to account for both nucleic acid and ligand flexibility. In this approach, with both the ligand and the receptor permitted some flexibility, they can bind one another via an induced fit, as the flexible ligand probes the surface of the receptor. A possible ligand can explore a low-energy path at the surface of the receptor by carrying out energy minimization with root-mean-square-distance constraints. Our procedure was tested on 57 RNA complexes (33 crystal and 24 NMR structures); this is the largest data set to date to reproduce experimental RNA binding poses. With our procedure, the lowest-energy conformations reproduced the experimental binding poses within an atomic root-mean-square deviation of 2.5 angstrom for 74% of tested complexes.