三维生物相关谱的计算及其在药物发现中的应用

项目名称： 三维生物相关谱的计算及其在药物发现中的应用

项目编号： No.21275061

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 孔德信

作者单位： 华中农业大学

项目金额： 80万元

中文摘要： 生物相关谱(BRS)可以作为多元分子描述符，建立有效的药物吸收、分布以及成药性预测模型。但是，药物分子和靶标之间是三维空间的相互作用，BRS的二维本质限制了它对结构特异性体系(如生物活性类别、急性毒性等)的预测能力。本项目将在前期研究的基础上把BRS的计算提高到三维结构的水平。首先，对蛋白质配基数据库sc-PDB进行三维相似性矩阵的计算和多样性采样，建立三维生物相关代表性化合物库；然后，通过基于模板的柔性分子叠合和生物相关算法，实现三维生物相关性(BR-3D)和三维生物相关谱(BRS-3D)的计算；再后，分别检验BR-3D在区分活性化合物、BRS-3D在复杂疾病的多靶标药物设计(以II型糖尿病药物筛选为例)和急性毒性预测中的应用；最后，对验证有效的预测模型，实现网络计算服务。本项目的研究对于备筛化合物库的优化、复杂疾病的多靶标药物设计和药物的化学空间分析等都具有重要的指导意义。

中文关键词： 三维生物相关谱；分子相似性谱；配基谱析；分子描述符；虚拟筛选

英文摘要： Biological relevance spectrum (BRS) is proved to be effective as a multivariate descriptor for drug design, which is useful in absorption, distribution, drug-likeness prediction. However, the interaction between ligands and biological macromolecule is three-dimensional force field affinity. The innate 2D character of BRS limited its application in structurally specific biological activity or toxcity prediction for drug discovery. In this program, we will improve the algorithm of BR/BRS to three dimensional level. Firstly, based on 3D molecular similarity (structural superposition) matrix calculation, 3D biologically relevant representative compound database will be constructed with PDB ligand database, sc-PDB. Secondly, BR-3D and BRS-3D will be calculated based on 3D molecular superposition and the same algorithm used in 2D BR/BRS calculation. Then, potential of BR-3D and BRS-3D on drug discovery and design will be investigated with bioactive compound classification, multi-targeted drug design (type II diabetes drugs as an example) and acute toxicity prediction. At last, internet services for proved models will be provided. Compared with finger-print or property descriptor based 2D similarity calculation, the physical meaning of 3D structural superimposition is easier to be understood. Lots of studies also pr

英文关键词： Three-Dimensional Biologically Relevant Spectrum；molecular similarity profile；ligand profiling；molecular descriptor；virtual screening