European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
J R Soc Interface. 2012 Dec 7;9(77):3196-207. doi: 10.1098/rsif.2012.0569. Epub 2012 Aug 29.
One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated K(i) ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification.
现代药物发现的最初步骤之一是确定能够抑制具有治疗意义的靶大分子的小分子有机分子。这些命中的一小部分进一步开发为先导化合物，而先导化合物最终可能会导致上市药物。用于此任务的常用筛选方案是高通量筛选（HTS）。然而，HTS 对抗菌靶标的性能通常并不令人满意，成本高，命中率低。在这里，我们提出了一种新颖的计算方法，该方法能够通过以省时，省钱和高效的方式搜索异常大的分子数据库，识别出高比例结构多样的抑制剂。该虚拟筛选方法在两种抗菌靶标（结核分枝杆菌和链霉菌的 II 型脱氢酶）的两个版本上进行了前瞻性测试，HTS 并未对此类靶标提供令人满意的结果，因此几乎所有已知的抑制剂均为同一核心支架的衍生物。总体而言，我们的方案鉴定了 100 种新抑制剂，其计算的 K(i)值范围为 4 至 250 μM（针对每个靶标版本的确认命中率为 60％和 62％）。最重要的是，发现了 50 多种新的活性分子支架，这突显了广泛应用经过前瞻性验证的计算筛选工具可能为抗菌命中识别带来的好处。
