Department of Medicinal Chemistry, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, USA.
J Chem Inf Model. 2011 Aug 22;51(8):1931-41. doi: 10.1021/ci100475y. Epub 2011 Jul 22.
The method of conserved core substructure matching (CSM) for the overlay of protein-ligand complexes is described. The method relies upon distance geometry to align structurally similar substructures without regard to sequence similarity onto substructures from a reference protein empirically selected to include key determinants of binding site location and geometry. The error in ligand position is reduced in reoriented ensembles generated with CSM when compared to other overlay methods. Since CSM can only succeed when the selected core substructure is geometrically conserved, misalignments only rarely occur. The method may be applied to reliably overlay large numbers of protein-ligand complexes in a way that optimizes ligand position at a specific binding site or subsite or to align structures from large and diverse protein families where the conserved binding site is localized to only a small portion of either protein. Core substructures may be complex and must be chosen with care. We have created a database of empirically selected core substructures to demonstrate the utility of CSM alignment of ligand binding sites in important drug targets. A Web-based interface can be used to apply CSM to align large collections of protein-ligand complexes for use in drug design using these substructures or to evaluate the use of alternative core substructures that may then be shared with the larger user community. Examples show the benefit of CSM in the practice of structure-based drug design.
描述了一种用于蛋白质-配体复合物叠加的保守核心子结构匹配（CSM）方法。该方法依赖距离几何来对齐结构相似的子结构，而不考虑序列相似性，而是将子结构从经验上选择的参考蛋白质上的子结构对齐，该参考蛋白质包括结合位点位置和几何形状的关键决定因素。与其他叠加方法相比，CSM 生成的重新定向集合中的配体位置误差减小。由于 CSM 只能在选择的核心子结构在几何上保守时才成功，因此很少出现错位。该方法可用于可靠地叠加大量蛋白质-配体复合物，以优化特定结合位点或亚位点处的配体位置，或者对齐来自大型和多样化蛋白质家族的结构，其中保守的结合位点仅局限于蛋白质的一小部分。核心子结构可能很复杂，必须谨慎选择。我们创建了一个经验选择的核心子结构数据库，以演示 CSM 在重要药物靶标中配体结合位点对齐的实用性。可以使用基于 Web 的界面将 CSM 应用于对齐大型蛋白质-配体复合物集合，以在使用这些子结构进行药物设计时使用，或者评估替代核心子结构的使用，然后可以与更大的用户社区共享。示例显示了 CSM 在基于结构的药物设计实践中的优势。
