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High Impact: The Role of Promiscuous Binding Sites in Polypharmacology

1
Université de Paris, Biologie Fonctionnelle et Adaptative, UMR 8251, CNRS, ERL U1133, INSERM, Computational Modeling of Protein Ligand Interactions, F-75013 Paris, France
2
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
3
Laboratoire Génomique Bioinformatique et Chimie Moléculaire, EA 7528, Conservatoire National des Arts et Métiers, F-75003 Paris, France
*
Author to whom correspondence should be addressed.
Academic Editor: J.B. Brown
Molecules 2019, 24(14), 2529; https://doi.org/10.3390/molecules24142529
Received: 3 June 2019 / Revised: 27 June 2019 / Accepted: 27 June 2019 / Published: 10 July 2019
(This article belongs to the Special Issue Computational Chemical Biology)
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PDF [6120 KB, uploaded 11 July 2019]
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Abstract

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. View Full-Text
Keywords: proteochemometrics; multi-targets; drug promiscuity; druggable binding site; descriptors; polypharmacology proteochemometrics; multi-targets; drug promiscuity; druggable binding site; descriptors; polypharmacology
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    Doi: 10.6084/m9.figshare.8313185
    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.

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