High Impact: The Role of Promiscuous Binding Sites in Polypharmacology
AbstractThe 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. View Full-Text
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Description: DBS4 Datastet. The 7.267 pockets are named according to the ligand (HET code from the Protein Data Bank), the protein (PDB code), the letter of the protein chain, and the numero of the ligand by chain (differs from 1 if there is more than 1 ligand in the chain), separated by underscores. The pocket cluster and ligand cluster columns are the name of each clusters, respectively 481 pocket clusters and 1.969 ligand clusters. The name of the 3.488 ligands correspond to the HET codes from the Protein Data Bank. The promiscuity of Druggable Binding Site (DBS), corresponding to pocket clusters) is leveled in 3 categories : Selective (S), Moderately Promiscuous (MP) and Highly Promiscuous (HP) meaning that DBS interact with respectively only one, two or three, or more than three ligand-clusters. The promiscuity of Ligand clusters is leveled in 2 categories : Selective (S), they bind to only one DBS and Promiscuous (Prom), they bind to several DBS.
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Cerisier, N.; Petitjean, M.; Regad, L.; Bayard, Q.; Réau, M.; Badel, A.; Camproux, A.-C. High Impact: The Role of Promiscuous Binding Sites in Polypharmacology. Molecules 2019, 24, 2529.
Cerisier N, Petitjean M, Regad L, Bayard Q, Réau M, Badel A, Camproux A-C. High Impact: The Role of Promiscuous Binding Sites in Polypharmacology. Molecules. 2019; 24(14):2529.Chicago/Turabian Style
Cerisier, Natacha; Petitjean, Michel; Regad, Leslie; Bayard, Quentin; Réau, Manon; Badel, Anne; Camproux, Anne-Claude. 2019. "High Impact: The Role of Promiscuous Binding Sites in Polypharmacology." Molecules 24, no. 14: 2529.
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