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首页> 外文期刊>Computational Biology and Bioinformatics, IEEE/ACM Transactions on >Toward a Robust Search Method for the Protein-Drug Docking Problem
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Toward a Robust Search Method for the Protein-Drug Docking Problem

机译：寻求蛋白质-药物对接问题的鲁棒搜索方法

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摘要

Predicting the binding mode(s) of a drug molecule to a target receptor is pivotal in structure-based rational drug design. In contrast to most approaches to solve this problem, the idea in this paper is to analyze the search problem from a computational perspective. By building on top of an existing docking tool, new methods are proposed and relevant computational results are proven. These methods and results are applicable for other place-and-join frameworks as well. A fast approximation scheme for the docking of rigid fragments is described that guarantees certain geometric approximation factors. It is also demonstrated that this can be translated into an energy approximation for simple scoring functions. A polynomial time algorithm is developed for the matching phase of the docked rigid fragments. It is demonstrated that the generic matching problem is NP-hard. At the same time, the optimality of the proposed algorithm is proven under certain scoring function conditions. The matching results are also applicable for some of the fragment-based de novo design methods. On the practical side, the proposed method is tested on 829 complexes from the PDB. The results show that the closest predicted pose to the native structure has the average RMS deviation of 1.06 Å.
机译：在基于结构的合理药物设计中，预测药物分子与靶受体的结合方式至关重要。与大多数解决此问题的方法相反，本文的想法是从计算角度分析搜索问题。通过在现有对接工具的基础上，提出了新方法，并证明了相关的计算结果。这些方法和结果也适用于其他放置和连接框架。描述了一种对接刚性片段的快速逼近方案，该方案可确保某些几何逼近因子。还证明了这可以转化为简单评分函数的能量近似。针对对接的刚性片段的匹配阶段，开发了多项式时间算法。证明了一般匹配问题是NP难的。同时，在一定的评分函数条件下，证明了算法的最优性。匹配结果也适用于某些基于片段的从头设计方法。在实践方面，对PDB的829个复合物进行了测试。结果表明，最接近自然结构的预测姿态的平均RMS偏差为1.06Å。

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