Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification.
Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification.
复制标题
DOI：
10.1098/rsif.2012.0569
复制
发表时间：
2012-12-07
期刊：
影响因子：
--
通讯作者：
Mitchell JB
中科院分区：
文献类型：
--
作者：
Ballester PJ;Mangold M;Howard NI;Robinson RL;Abell C;Blumberger J;Mitchell JB
现代药物发现的最初步骤之一是鉴定能够抑制具有治疗意义的目标大分子的小有机分子。这些命中的一小部分被进一步开发成先导化合物，这反过来又可能最终导致上市药物。用于该任务的常用筛选方案是高通量筛选（HTS）。然而，HTS针对抗菌靶标的性能通常不令人满意，具有高成本和低命中识别率。在这里，我们提出了一种新的计算方法，能够识别高比例的结构多样的抑制剂，通过搜索异常大的分子数据库中的时间，成本和资源效率的方式。该虚拟筛选方法在两种版本的抗菌靶标（来自结核分枝杆菌和天蓝色链霉菌的II型脱氢醌酶）上进行了前瞻性测试，HTS没有提供令人满意的结果，因此实际上所有已知的抑制剂都是相同核心支架的衍生物。总体而言，我们的方案确定了100种新的抑制剂，计算的Ki范围为4至250 μM（针对每个版本的靶标，确认的命中率分别为60%和62%）。最重要的是，发现了超过50种新的活性分子支架，强调了前瞻性验证的计算机筛选工具的广泛应用可能为抗菌命中识别带来的好处。
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 Ki 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.
登录
查看更多内容
影响因子：
11.3
作者：
Ambur OH;Davidsen T;Frye SA;Balasingham SV;Lagesen K;Rognes T;Tønjum T
通讯作者：
Tønjum T
影响因子：
5.6
作者：
JONES, G;WILLETT, P;GLEN, RC
通讯作者：
GLEN, RC
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
5.5
作者：
Blomberg, L. Mattias;Mangold, Martina;Blumberger, Jochen
通讯作者：
Blumberger, Jochen
影响因子：
5.6
作者：
Li L;Wang B;Meroueh SO
通讯作者：
Meroueh SO