Université de Paris, Biologie Fonctionnelle et Adaptative, UMR 8251, CNRS, ERL U1133, INSERM, Computational Modeling of Protein Ligand Interactions, F-75013 Paris, France.
Centre de Recherche des Cordeliers, Sorbonne Universités, INSERM, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, F-75006 Paris, France.
Molecules. 2019 Jul 10;24(14):2529. doi: 10.3390/molecules24142529.
The literature focuses on drug promiscuity, which is a drug's ability to bind to several targets, because it plays an essential role in polypharmacology. However, little work has been completed regarding binding site promiscuity, even though its properties are now recognized among the key factors that impact drug promiscuity. Here, we quantified and characterized the promiscuity of druggable binding sites from protein-ligand complexes in the high quality Mother Of All Databases while using statistical methods. Most of the sites (80%) exhibited promiscuity, irrespective of the protein class. Nearly half were highly promiscuous and able to interact with various types of ligands. The corresponding pockets were rather large and hydrophobic, with high sulfur atom and aliphatic residue frequencies, but few side chain atoms. Consequently, their interacting ligands can be large, rigid, and weakly hydrophilic. The selective sites that interacted with one ligand type presented less favorable pocket properties for establishing ligand contacts. Thus, their ligands were highly adaptable, small, and hydrophilic. In the dataset, the promiscuity of the site rather than the drug mainly explains the multiple interactions between the drug and target, as most ligand types are dedicated to one site. This underlines the essential contribution of binding site promiscuity to drug promiscuity between different protein classes.
文献主要关注药物混杂性，即药物与多个靶点结合的能力，因为它在多药理学中起着至关重要的作用。然而，尽管现在已经认识到结合位点混杂性是影响药物混杂性的关键因素之一，但针对其特性的研究却很少。在这里，我们使用统计方法对高质量的“所有数据库之母”中的蛋白质-配体复合物中的可成药性结合位点的混杂性进行了量化和特征描述。大多数（80%）位点表现出混杂性，与蛋白质类别无关。近一半的位点具有高度混杂性，能够与各种类型的配体相互作用。相应的口袋较大且疏水性强，硫原子和脂肪族残基频率较高，但侧链原子较少。因此，它们相互作用的配体可以较大、刚性且弱亲水性。与一种配体类型相互作用的选择性位点，其口袋性质不利于建立配体接触。因此，它们的配体具有高度适应性、较小和较强的亲水性。在数据集内，与靶标相互作用的配体类型较少，而不是药物的混杂性主要解释了药物与靶标之间的多种相互作用，因为大多数配体类型都专门针对一个位点。这突显了结合位点混杂性对不同蛋白质类别之间药物混杂性的重要贡献。
