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

为了具有生物活性，小分子、蛋白质和其他细胞成分必须物理上适合于它们在靶标内的结合部位(S)。一个世纪前，费舍尔将这一事件描述为一种锁和钥匙的契合。然而，在达到其准确的结合位置时，配体(与另一种分子结合的分子)与各种结构和功能的各种细胞成分相互作用。所有这些事件都增加了配体，特别是外源性细胞来源的小分子(如合成药物)与不希望看到的脱靶物质(S)结合的可能性，从而改变了它们的细胞功能。正如2013年诺贝尔化学奖所承认的那样，计算机模拟目前非常适合于解决这些问题。我们研究的长期目标是评估小分子与关键的细胞外靶点的相互作用。

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.