Chen Jing, Ma Xiaomin, Yuan Yaxia, Pei Jianfeng, Lai Luhua
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Curr Pharm Des. 2014;20(8):1192-200. doi: 10.2174/13816128113199990065.
Rational design for chemical compounds targeting protein-protein interactions has grown from a dream to reality after a decade of efforts. There are an increasing number of successful examples, though major challenges remain in the field. In this paper, we will first give a brief review of the available methods that can be used to analyze protein-protein interface and predict hot spots for chemical ligand design. New developments of binding sites detection, ligandability and hot spots prediction from the author's group will also be described. Pocket V.3 is an improved program for identifying hot spots in protein-protein interface using only an apo protein structure. It has been developed based on Pocket V.2 that can derive receptor-based pharmacophore model for ligand binding cavity. Given similarities and differences between the essence of pharmacophore and hot spots for guiding design of chemical compounds, not only energetic but also spatial properties of protein-protein interface are used in Pocket V.3 for dealing with protein-protein interface. In order to illustrate the capability of Pocket V.3, two datasets have been used. One is taken from ASEdb and BID having experimental alanine scanning results for testing hot spots prediction. The other is taken from the 2P2I database containing complex structures of protein-ligand binding at the original protein-protein interface for testing hot spots application in ligand design.
经过十年的努力，针对蛋白质-蛋白质相互作用的化合物合理设计已从梦想变为现实。成功的例子越来越多，尽管该领域仍存在重大挑战。在本文中，我们将首先简要回顾可用于分析蛋白质-蛋白质界面并预测化学配体设计热点的现有方法。还将介绍作者团队在结合位点检测、配体可及性和热点预测方面的新进展。Pocket V.3是一个仅使用无配体蛋白质结构来识别蛋白质-蛋白质界面热点的改进程序。它是在Pocket V.2的基础上开发的，Pocket V.2可以导出用于配体结合腔的基于受体的药效团模型。鉴于药效团本质与指导化合物设计的热点之间的异同，Pocket V.3不仅利用蛋白质-蛋白质界面的能量性质，还利用其空间性质来处理蛋白质-蛋白质界面。为了说明Pocket V.3的能力，使用了两个数据集。一个取自ASEdb和BID，有实验性丙氨酸扫描结果用于测试热点预测。另一个取自2P2I数据库，该数据库包含在原始蛋白质-蛋白质界面处蛋白质-配体结合的复杂结构，用于测试热点在配体设计中的应用。
