Bolz Sarah Naomi, Schake Philipp, Stitz Celina, Schroeder Michael
Biotechnological Center, CMCB and scads.ai, Dresden, Germany.
Expert Opin Drug Discov. 2025 Sep 16:1-16. doi: 10.1080/17460441.2025.2557599.
Promiscuity of drugs and targets plays an important role in drug-target prediction, ranging from the explanation of side effects to their exploitation in drug repositioning. A specific form of promiscuity concerns drugs, which interfere with protein-protein interactions. With the rising importance of such drugs in drug discovery and with the large-scale availability of structural data, the question arises on the structural basis of this form of promiscuity and the commonalities of the underlying protein-ligand (PLI) and protein-protein interactions (PPI).
The authors applied the protein-ligand interaction profiler, PLIP, to experimental and predicted structures and characterize drugs in clinical trials, which target PPI.
PPIs generally involve more non-covalent interactions than PLI with overlapping interaction patterns and key binding site residues. In contrast to experimental structures, predicted structures fall short in accurately capturing interaction details at the interface.
Taken together, our analysis shows that PPIs and PLIs have sufficient commonalities to merit future work into computational screenings for drugs targeting PPIs. It will be key to further improve structure prediction, specifically for binding site details.
药物与靶点的多配体性在药物靶点预测中起着重要作用，涵盖从副作用解释到药物重新定位应用等方面。一种特定形式的多配体性涉及干扰蛋白质 - 蛋白质相互作用的药物。随着这类药物在药物研发中的重要性不断提升以及结构数据的大规模可得性，关于这种多配体性形式的结构基础以及潜在蛋白质 - 配体（PLI）和蛋白质 - 蛋白质相互作用（PPI）的共性问题随之出现。
作者将蛋白质 - 配体相互作用分析工具PLIP应用于实验结构和预测结构，并对临床试验中靶向PPI的药物进行特征描述。
与具有重叠相互作用模式和关键结合位点残基的PLI相比，PPI通常涉及更多非共价相互作用。与实验结构相比，预测结构在准确捕捉界面处的相互作用细节方面存在不足。
综合来看，我们的分析表明PPI和PLI具有足够的共性，值得未来针对靶向PPI的药物进行计算筛选研究。进一步改进结构预测，特别是结合位点细节的预测，将是关键所在。
