构建药物-靶标亲合性打分函数的评价方法体系  

Development of a high-quality benchmark for scoring function assessment

作　　者：刘志海[1] 李婕[1] 韩莉[1] 李嫣[1] 王任小[1] 

机构地区：[1]生命有机化学国家重点实验室,生命的化学基础协同创新中心,中国科学院上海有机化学研究所,上海200032

出　　处：《中国科学：化学》2015年第9期949-960,共12页SCIENTIA SINICA Chimica

摘　　要：定量计算药物-靶标亲合性一直是分子靶向药物设计中的核心问题之一.亲合性打分函数适用范围宽、计算速度快且精度良好,特别适合与分子对接等方法联用,在药物研发中得到了广泛的应用.经过20多年的发展,目前存在数量繁多的打分函数,这些方法难免良莠不齐.建立客观公正的针对打分函数性能的评价体系,不仅可以帮助用户做出合理的选择,也为发展打分函数的理论研究人员提供依据,因此是打分函数研究领域中的一个基础问题.近年来,我们逐步发展了评价药物-靶标亲合性打分函数性能的方法体系(comparative assessment of scoring functions,CASF),为解决该问题提供了一种可行的方案.我们提出了一整套衡量打分函数性能的基本指标,为每种指标设计了相应的定量方法,并确立了将打分过程与构象采样过程分开处理的原则.我们的方法体系中所使用的测试集,源自对PDBbind-CN数据库中蛋白-配体复合物样本的层层筛选,质量较高并且具备结构多样性的特点.与前人的类似工作相比,我们的方法体系具有较强的系统性和先进性,受到了国内外同行的广泛认可和应用.本文介绍了我们建立的CASF方法体系的设计思想、获得的重要研究成果以及学术影响.Quantitative computation of drug-target binding affinity has been one of the key problems in molecular- targeted drug design. Scoring functions are fast, robust, and fairly accurate and thus are widely applied in drug design. Not surprisingly, a large number of scoring functions have been developed over the past twenty years. The performance of these methods is certainly not equal. An objective benchmark for assessing scoring functions is thus desired by the users of scoring function for making wise choice among available options. It is also desired by the developers of scoring function for obtaining useful guidance. In recent years, we have established a benchmark, namely Comparative Assessment Scoring Function （CASF）, to tackle this critical problem. We proposed a set of indicators for measuring the performance of scoring function and developed evaluation methods accordingly. Very importantly, the scoring process was separated from the conformational sampling process in order to evaluate scoring functions on a common ground. The test set used in CASF, which consisted of non-redundant protein-ligand complexes with high-quality crystal structure and reliable binding data, was carefully selected from the PDBbind-CN database. Compare to the similar benchmarks published by other researchers, our CASF benchmark is more advanced, which has been applied by other researchers since published. We describe the basic methods, evaluation results, and international impact of our CASF benchmark in this review article.

关 键 词：药物-靶标亲合性 打分函数 评价体系 CASF PDBbind-CN 分子靶向药物设计 

分 类 号：TQ460.1[化学工程—制药化工]