Drug Design and Bioinformatics Lab, Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria.
Int J Mol Sci. 2024 Jun 28;25(13):7124. doi: 10.3390/ijms25137124.
Binding affinity is a fundamental parameter in drug design, describing the strength of the interaction between a molecule and its target protein. Accurately predicting binding affinity is crucial for the rapid development of novel therapeutics, the prioritization of promising candidates, and the optimization of their properties through rational design strategies. Binding affinity is determined by the mechanism of recognition between proteins and ligands. Various models, including the lock and key, induced fit, and conformational selection, have been proposed to explain this recognition process. However, current computational strategies to predict binding affinity, which are based on these models, have yet to produce satisfactory results. This article explores the connection between binding affinity and these protein-ligand interaction models, highlighting that they offer an incomplete picture of the mechanism governing binding affinity. Specifically, current models primarily center on the binding of the ligand and do not address its dissociation. In this context, the concept of ligand trapping is introduced, which models the mechanisms of dissociation. When combined with the current models, this concept can provide a unified theoretical framework that may allow for the accurate determination of the ligands' binding affinity.
结合亲和力是药物设计中的一个基本参数，描述了分子与其靶蛋白之间相互作用的强度。准确预测结合亲和力对于新型治疗药物的快速开发、有前途的候选药物的优先级排序以及通过合理的设计策略优化其性质至关重要。结合亲和力由蛋白质和配体之间的识别机制决定。已经提出了各种模型，包括锁和钥匙、诱导契合和构象选择，以解释这种识别过程。然而，目前基于这些模型预测结合亲和力的计算策略尚未产生令人满意的结果。本文探讨了结合亲和力与这些蛋白质-配体相互作用模型之间的联系，强调它们提供了对决定结合亲和力的机制的不完整描述。具体来说，目前的模型主要集中在配体的结合上，而没有解决其解离的问题。在这种情况下，引入了配体捕获的概念，该概念模拟了解离的机制。当与当前模型结合使用时，该概念可以提供一个统一的理论框架，可能允许准确确定配体的结合亲和力。
