Identifying and Characterizing Binding Sites and Assessing Druggability
Identifying and Characterizing Binding Sites and Assessing Druggability
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DOI：
10.1021/ci800324m
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发表时间：
2009-02-01
影响因子：
5.6
通讯作者：
Halgren, Thomas A.
中科院分区：
文献类型：
--
作者：
Halgren, Thomas A.
结合部位的鉴定和表征是基于结构的药物设计过程中的关键。在某些情况下，可能没有关于感兴趣目标的结合位点的任何信息。在其他情况下，通过计算或实验手段已经确定了假定的结合部位，但靶标的可药性尚不清楚。即使已知特定靶点的位置，也可能希望找到更多靶点，其靶向可以产生所需的生物反应。一种名为Sitemap的新程序被提出，用于识别和分析结合位点，并用于预测目标药物的可药性。在大规模验证中，Sitemap在86%的情况下正确地将已知的结合位点识别为排名最高的位置，其中最好的结果(>；98%)来自与亚纳摩尔亲和力结合的配体。此外，用于结合位点识别的分数的修改版本允许Sitemap根据蛋白质与被动吸收的小分子紧密结合的能力来准确地对蛋白质的可药性进行分类。在描述结合位点时，Sitemap提供了定量和图形信息，这些信息可以帮助指导在铅发现应用中批判性地评估虚拟命中，或在铅优化环境中修改配体结构以增强效力或改善物理性质。
Identification and characterization of binding sites is key in the process of structure-based drug design. In some cases there may not be any information about the binding site for a target of interest. In other cases, a putative binding site has been identified by computational or experimental means, but the druggability of the target is not known. Even when a site for a given target is known, it may be desirable to find additional sites whose targeting could produce a desired biological response. A new program, called SiteMap, is presented for identifying and analyzing binding sites and for predicting target druggability. In a large-scale validation, SiteMap correctly identifies the known binding site as the top-ranked site in 86% of the cases, with best results (>98%) coming for sites that bind ligands with subnanomolar affinity. In addition, a modified version of the score employed for binding-site identification allows SiteMap to accurately classify the druggability of proteins as measured by their ability to bind passively absorbed small molecules tightly. In characterizing binding sites, SiteMap provides quantitative and graphical information that can help guide efforts to critically assess virtual hits in a lead-discovery application or to modify ligand structure to enhance potency or improve physical properties in a lead-optimization context.