Biomedicinal Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), Koto-ku, Tokyo, Japan.
Curr Top Med Chem. 2010;10(6):680-94. doi: 10.2174/156802610791111452.
For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naïve protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, post-processing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.
对于基于片段的药物开发，命中（活性）化合物的预测和命中化合物的对接构象（蛋白质-配体复合物结构）预测都很重要，因为在发现命中化合物之后必须基于蛋白质-配体复合物结构进行化学修饰（片段连接、片段进化）。然而，基于片段的药物开发中，基于蛋白质-化合物对接的原始对接计算在对接构象预测方面的准确性较差。因此，需要对蛋白质-化合物对接进行后处理。最近，已经提出了几种用于蛋白质-化合物对接后处理的方法。在基于片段的药物开发中，化合物比传统药物筛选中的化合物更小。这使得进行蛋白质-化合物对接计算变得困难。已经报道了一种避免该问题的方法。蛋白质-配体结合自由能估计对于减少命中片段的化学修饰过程很有用。已经提出了几种用于高精度估计蛋白质-配体结合自由能的预测方法。本文总结了用于对接构象预测的各种计算方法及其在基于片段的药物开发中的有用性。
