Atomistic Computational Models To Evaluate Protein-Ligand Off-Target Interactions

为了具有生物活性，小分子、蛋白质和其他细胞组分必须在物理上适合其靶标内的结合位点。一个世纪前，费舍尔将这一事件描述为一个锁和钥匙的配合。然而，在到达其精确的结合位置时，配体（与另一个分子结合的分子）与各种结构和功能的各种细胞组分相互作用。所有这些事件增加了配体，特别是外源性细胞来源的小分子（例如合成药物）与不期望的脱靶结合的可能性，改变了它们的细胞功能。计算机模拟目前非常适合解决这些问题，这一点在2013年诺贝尔化学奖中得到了认可。我们研究的长期目标是评估小分子与关键细胞脱靶的相互作用。

To be biologically active, small molecules, proteins and other cellular components must physically fit into their binding site(s) within their targets. A century ago, Fischer described this event as a lock-and-key fit. However, in reaching its precise binding location, a ligand (a molecule that binds to another) interacts with a variety of cellular components of various structures and functions. All these events increase the probability for a ligand, particularly a small molecule of exogenous cellular origin (e.g. synthetic drugs) to bind to an undesired off-target(s), altering their cellular functions. Computer simulations are currently well suited to address these problems as recognized with the 2013 Nobel Prize in Chemistry. The long-term goal of our research is to evaluate the interaction of small molecules with critical cellular off-targets.