Miller M D, Kearsley S K, Underwood D J, Sheridan R P
Molecular Systems Department, Merck Research Laboratories, West Point, PA 19486.
J Comput Aided Mol Des. 1994 Apr;8(2):153-74. doi: 10.1007/BF00119865.
We present a system, FLOG (Flexible Ligands Oriented on Grid), that searches a database of 3D coordinates to find molecules complementary to a macromolecular receptor of known 3D structure. The philosophy of FLOG is similar to that reported for DOCK [Shoichet, B.K. et al., J. Comput. Chem., 13 (1992) 380]. In common with that system, we use a match center representation of the volume of the binding cavity and we use a clique-finding algorithm to generate trial orientations of each candidate ligand in the binding site. Also we use a grid representation of the receptor to assess the fit of each orientation. We have introduced a number of novel features within this paradigm. First, we address ligand flexibility by including up to 25 explicit conformations of each structure in our databases. Nonhydrogen atoms in each database entry are assigned one of seven atom types (anion, cation, donor, acceptor, polar, hydrophobic and other) based on their local bonded chemical environments. Second, we have devised a new grid-based scoring function compatible with this 'heavy atom' representation of the ligands. This includes several potentials (electrostatic, hydrogen bonding, hydrophobic and van der Waals) calculated from the location of the receptor atoms. Third, we have improved the fitting stage of the search. Initial dockings are generated with a more efficient clique-finding algorithm. This new algorithm includes the concept of 'essential points', match centers that must be paired with a ligand atom. Also, we introduce the use of a rapid simplex-based rigid-body optimizer to refine the orientations. We demonstrate, using dihydrofolate reductase as a sample receptor, that the FLOG system can select known inhibitors from a large database of drug-like compounds.
我们提出了一种名为FLOG（基于网格的柔性配体）的系统，该系统通过搜索三维坐标数据库来寻找与已知三维结构的大分子受体互补的分子。FLOG的原理与DOCK系统[Shoichet, B.K.等人，《计算化学杂志》，13(1992)380]类似。与该系统一样，我们使用结合腔体积的匹配中心表示法，并使用团簇查找算法来生成每个候选配体在结合位点的试验取向。此外，我们使用受体的网格表示法来评估每个取向的契合度。在这个范式中，我们引入了许多新颖的特性。首先，我们通过在数据库中包含每个结构多达25种明确的构象来处理配体的灵活性。每个数据库条目中的非氢原子根据其局部键合化学环境被分配为七种原子类型之一（阴离子、阳离子、供体、受体、极性、疏水和其他）。其次，我们设计了一种与这种配体的“重原子”表示法兼容的基于网格的新评分函数。这包括从受体原子位置计算出的几种势能（静电、氢键、疏水和范德华力）。第三，我们改进了搜索的拟合阶段。初始对接使用更高效的团簇查找算法生成。这种新算法包括“关键点”的概念，即必须与配体原子配对的匹配中心。此外，我们引入了基于快速单纯形的刚体优化器来优化取向。我们以二氢叶酸还原酶作为样本受体进行演示，结果表明FLOG系统可以从大量类药物化合物数据库中筛选出已知的抑制剂。
