Lee Matthew R, Sun Yaxiong
Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799.
J Chem Theory Comput. 2007 May;3(3):1106-19. doi: 10.1021/ct6003406.
Docking methods are typically used within the biopharmaceutical industry for the challenging purposes of suggesting putative binding modes of new chemotypes and for virtual screening. When attempting to satisfy the far more simplistic yet fundamentally important goal of reproducing and identifying the correct binding mode from a cocrystal, all docking methods fail at a rather significant rate, demonstrating room for further improvement in docking methodology. We report a hierarchical method that yields results comparable to the industry-leading docking packages GOLD, Glide, and Surflex. By first using a fast, simple, well-established method, UCSF DOCK 4.0, to rigidly dock conformational ensembles, we successfully generate the correct binding mode in all but 4 of a standard, publicly available set of 79 cocrystals from the PDB. Among these 4 failures (1glq, 1tmn, 1rds, and 8gch), all are highly flexible, highly charged, and not druglike. Subsequently, all resultant docking poses were optimized and scored in the protein with molecular mechanics, using a standard MMGB energy function. In total, this hierarchical method identified the correct binding in 71 of 79 cases (90%), an unprecedented level of accuracy on this highly benchmarked test set. Furthermore, the publicly available energy functions employ only physically based force fields without parameter fitting from this or any other docking test sets.
对接方法通常用于生物制药行业，以实现具有挑战性的目标，即推测新化学型的假定结合模式和进行虚拟筛选。当试图实现一个更为简单但从根本上来说却很重要的目标，即从共晶体中重现并识别正确的结合模式时，所有对接方法都有相当高的失败率，这表明对接方法仍有进一步改进的空间。我们报告了一种分层方法，其产生的结果可与行业领先的对接软件包GOLD、Glide和Surflex相媲美。通过首先使用一种快速、简单且成熟的方法UCSF DOCK 4.0对构象集合进行刚性对接，我们在来自蛋白质数据银行（PDB）的一组79个标准公开共晶体中，除了4个之外，成功生成了所有共晶体的正确结合模式。在这4个失败案例（1glq、1tmn、1rds和8gch）中，所有案例都具有高度的灵活性、高电荷性且不像药物。随后，使用标准的MMGB能量函数，通过分子力学对所有得到的对接姿势在蛋白质中进行优化和评分。总体而言，这种分层方法在79个案例中的71个（90%）中识别出了正确的结合，在这个经过高度基准测试的数据集上达到了前所未有的准确率。此外，公开可用的能量函数仅使用基于物理的力场，无需根据这个或任何其他对接测试集进行参数拟合。
