Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Protein Sci. 2024 Aug;33(8):e5116. doi: 10.1002/pro.5116.
Interactions between proteins and small organic compounds play a crucial role in regulating protein functions. These interactions can modulate various aspects of protein behavior, including enzymatic activity, signaling cascades, and structural stability. By binding to specific sites on proteins, small organic compounds can induce conformational changes, alter protein-protein interactions, or directly affect catalytic activity. Therefore, many drugs available on the market today are small molecules (72% of all approved drugs in the last 5 years). Proteins are composed of one or more domains: evolutionary units that convey function or fitness either singly or in concert with others. Understanding which domain(s) of the target protein binds to a drug can lead to additional opportunities for discovering novel targets. The evolutionary classification of protein domains (ECOD) classifies domains into an evolutionary hierarchy that focuses on distant homology. Previously, no structure-based protein domain classification existed that included information about both the interaction between small molecules or drugs and the structural domains of a target protein. This data is especially important for multidomain proteins and large complexes. Here, we present the DrugDomain database that reports the interaction between ECOD of human target proteins and DrugBank molecules and drugs. The pilot version of DrugDomain describes the interaction of 5160 DrugBank molecules associated with 2573 human proteins. It describes domains for all experimentally determined structures of these proteins and incorporates AlphaFold models when such structures are unavailable. The DrugDomain database is available online: http://prodata.swmed.edu/DrugDomain/.
蛋白质与小分子有机化合物之间的相互作用在调节蛋白质功能方面起着至关重要的作用。这些相互作用可以调节蛋白质行为的各个方面，包括酶活性、信号级联和结构稳定性。通过与蛋白质上的特定结合位点结合，小分子可以诱导构象变化、改变蛋白质-蛋白质相互作用，或直接影响催化活性。因此，目前市场上的许多药物都是小分子（过去 5 年中所有批准药物的 72%）。蛋白质由一个或多个结构域组成：这些结构域是单独或协同作用传递功能或适应性的进化单位。了解目标蛋白质的哪个（哪些）结构域与药物结合，可以为发现新的靶点提供更多机会。蛋白质结构域的进化分类（ECOD）将结构域分类为一个进化层次结构，重点关注遥远的同源性。以前，不存在基于结构的蛋白质结构域分类，该分类既包含小分子或药物与目标蛋白质结构域之间的相互作用信息，也包含这些信息。对于多结构域蛋白质和大复合物来说，这些数据尤其重要。在这里，我们介绍了 DrugDomain 数据库，该数据库报告了人类靶蛋白的 ECOD 与 DrugBank 分子和药物之间的相互作用。DrugDomain 的试用版描述了与 2573 个人类蛋白相关的 5160 种 DrugBank 分子的相互作用。它描述了这些蛋白质所有实验确定结构的结构域，并在没有这些结构时纳入了 AlphaFold 模型。DrugDomain 数据库可在线获取：http://prodata.swmed.edu/DrugDomain/。
