In this paper we describe our approaches to predict the binding mode of twenty BACE1 ligands as part of Grand Challenge 4 (GC4), organized by the Drug Design Data Resource. Calculations for all submissions (except for one, which used AutoDock4.2) were performed using AutoDock-GPU, the new GPU-accelerated version of AutoDock4 implemented in OpenCL, which features a gradient-based local search. The pose prediction challenge was organized in two stages. In Stage 1a, the protein conformations associated with each of the ligands were undisclosed, so we docked each ligand to a set of eleven receptor conformations, chosen to maximize the diversity of binding pocket topography. Protein conformations were made available in Stage 1b, making it a re-docking task. For all calculations, macrocyclic conformations were sampled on the fly during docking, taking the target structure into account. To leverage information from existing structures containing BACE1 bound to ligands available in the PDB, we tested biased docking and pose filter protocols to facilitate poses resembling those experimentally determined. Both pose filters and biased docking resulted in more accurate docked poses, enabling us to predict for both Stages 1a and 1b ligand poses within 2 Å RMSD from the crystallographic pose. Nevertheless, many of the ligands could be correctly docked without using existing structural information, demonstrating the usefulness of physics-based scoring functions, such as the one used in AutoDock4, for structure based drug design.

中文翻译：

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D3R 大挑战 4：使用 AutoDock-GPU 对 BACE1 配体进行前瞻性姿态预测。


在本文中，我们描述了预测 20 个 BACE1 配体的结合模式的方法，作为由药物设计数据资源组织的 Grand Challenge 4 (GC4) 的一部分。所有提交的计算（除了使用 AutoDock4.2 的一个）都是使用 AutoDock-GPU 执行的，AutoDock-GPU 是在 OpenCL 中实现的 AutoDock4 的新 GPU 加速版本，具有基于梯度的本地搜索。姿势预测挑战赛分为两个阶段。在第 1a 阶段，与每个配体相关的蛋白质构象均未公开，因此我们将每个配体与一组 11 个受体构象对接，选择这些构象以最大限度地提高结合袋拓扑结构的多样性。蛋白质构象在阶段 1b 中可用，使其成为一项重新对接任务。对于所有计算，大环构象都是在对接过程中动态采样的，同时考虑到目标结构。为了利用包含与 PDB 中可用配体结合的 BACE1 的现有结构的信息，我们测试了偏置对接和姿势过滤协议，以促进类似于实验确定的姿势。位姿过滤器和偏置对接都产生了更准确的对接位姿，使我们能够预测阶段 1a 和 1b 配体位姿与晶体学位姿的误差在 2 Å RMSD 以内。尽管如此，许多配体可以在不使用现有结构信息的情况下正确对接，这证明了基于物理的评分函数（例如 AutoDock4 中使用的函数）对于基于结构的药物设计的有用性。