Schrödinger, Sanali Infopark, 8-2-120/113 Banjara Hills, Hyderabad 500034, Andhra Pradesh, India.
J Chem Inf Model. 2011 Oct 24;51(10):2455-66. doi: 10.1021/ci2002704. Epub 2011 Sep 15.
Shape-based methods for aligning and scoring ligands have proven to be valuable in the field of computer-aided drug design. Here, we describe a new shape-based flexible ligand superposition and virtual screening method, Phase Shape, which is shown to rapidly produce accurate 3D ligand alignments and efficiently enrich actives in virtual screening. We describe the methodology, which is based on the principle of atom distribution triplets to rapidly define trial alignments, followed by refinement of top alignments to maximize the volume overlap. The method can be run in a shape-only mode or it can include atom types or pharmacophore feature encoding, the latter consistently producing the best results for database screening. We apply Phase Shape to flexibly align molecules that bind to the same target and show that the method consistently produces correct alignments when compared with crystal structures. We then illustrate the effectiveness of the method for identifying active compounds in virtual screening of eleven diverse targets. Multiple parameters are explored, including atom typing, query structure conformation, and the database conformer generation protocol. We show that Phase Shape performs well in database screening calculations when compared with other shape-based methods using a common set of actives and decoys from the literature.
基于形状的配体对齐和评分方法已被证明在计算机辅助药物设计领域具有重要价值。在这里，我们描述了一种新的基于形状的柔性配体叠加和虚拟筛选方法 Phase Shape，该方法能够快速产生准确的 3D 配体对齐，并有效地富集虚拟筛选中的活性化合物。我们描述了该方法的原理，它基于原子分布三元组的原理来快速定义试验对齐，然后对最佳对齐进行细化以最大化体积重叠。该方法可以在仅形状模式下运行，也可以包括原子类型或药效团特征编码，后者始终为数据库筛选产生最佳结果。我们将 Phase Shape 应用于灵活对齐与同一靶标结合的分子，结果表明，与晶体结构相比，该方法始终能够产生正确的对齐。然后，我们通过对十一个不同靶标的虚拟筛选来说明该方法识别活性化合物的有效性。我们探索了多个参数，包括原子类型、查询结构构象和数据库构象生成协议。与其他基于形状的方法相比，我们使用文献中的常见活性和虚拟化合物集来展示 Phase Shape 在数据库筛选计算中的良好性能。
