High Impact: The Role of Promiscuous Binding Sites in Polypharmacology
Abstract
:1. Introduction
2. Results
2.1. MOAD Druggable Binding Site Identification
2.1.1. MOAD Protein and Ligand Space
2.1.2. Druggable Binding Site Extraction
2.2. DBS Promiscuity Characterization
2.2.1. Druggable Binding Site Promiscuity Quantification
2.2.2. Binding Pocket Characteristics of DBS with Different Promiscuity Levels
2.2.3. Ligand Characteristics interacting with DBS with Different Promiscuity Levels
2.2.4. Pocket and Ligand Property Correspondence
2.3. DBS Promiscuity Contribution to Multiple Interactions of Ligands with Different MOAD Protein Classes
2.3.1. DBS Promiscuity Frequency Related to MOAD Protein Classes
2.3.2. Complementary Study of the Ligand–Cluster Promiscuity
2.3.3. Ligand–Cluster-DBS Interaction Network Examples
3. Discussion
4. Materials and Methods
4.1. MOAD Mining
4.1.1. Drug-Like Ligand Space Analysis and Clustering
Ligand Selection
Drug-Like Ligand Clustering and Description
4.1.2. Protein Space Analysis and Clustering
4.2. MOAD Druggable Binding Sites Extraction Protocol
4.2.1. Ligand-Binding Pocket Estimation
4.2.2. Superimposition of Mono-Chains from Each Homologous Chain Cluster
4.2.3. Cluster of Pockets Associated with a Druggable Binding Site
- let n(i) be the number of atoms of pocket i,
- let g(i) be the barycenter of the n(i) atoms of the pocket i,
- let d(i,j) be the Euclidean distance between g(i) and atom j of pocket i and the maximum value among the n(i) distances between the n(i) atoms and the barycenter g(i) of pocket i,
- let D and be the average value and standard deviation respectively of the population of the p observed values of and
- the cutoff value based on D and from the p pockets from the homologous chain cluster used is (1):
- Two pockets and are fall in the same Pocket-Cluster when meaning that the distance between barycenter and barycenter is lower than the cutoff value.
4.3. Promiscuity Characterization of Druggable Binding Site
4.3.1. Determination of DBS Promiscuity
4.3.2. Analysis of DBS Promiscuity in Terms of Pocket and Ligand Properties
4.4. Ligand–Cluster–DBS Interaction Network Illustration
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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DBS | ||||
---|---|---|---|---|
S | 100 | (20.8%) | 791 | (10.9%) |
MP | 166 | (34.5%) | 1447 | (19.9%) |
HP | 215 | (44.7%) | 5029 | (69.2%) |
Total | 481 | (100.0%) | 7267 | (100.0%) |
Ligand–Cluster | Occurrence (Frequency) | Tanimoto coefficient average (std. dev.) | Corresponding Ligands: Occurrence (Frequency) | |||
---|---|---|---|---|---|---|
Dedicated to | S DBS | 29 | (1.5%) | 0.24 (0.11) | 53 | (1.5%) |
MP DBS | 182 | (9.2%) | 0.29 (0.12) | 257 | (7.4%) | |
HP DBS | 1631 | (82.8%) | 0.33 (0.13) | 2621 | (75.1%) | |
Mixed | 127 | (6.4%) | 0.28 (0.13) | 557 | (16.0%) | |
ALL | 1969 | (100.0%) | 0.33 (0.13) | 3488 | (100.0%) |
Ligand–Cluster | Total | Selective | Promiscuous | Promiscuous | Promiscuous |
---|---|---|---|---|---|
Occurrence | Occurrence | Occurrence | Number of DBS: Average (sd) | Number of Protein Class: Average (sd) | |
Selective DBS | 68 | 29 | 39 | 6.7 (5.37) | 2.9 (1.45) |
MP DBS | 301 | 168 | 133 | 4.2 (3.68) | 2.1 (1.32) |
HP DBS | 1753 | 1421 | 332 | 3.2 (2.60) | 1.8 (1.02) |
All DBS1 | 1969 | 1618 | 351 | 3.1 (2.54) | 1.8 (1.02) |
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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. https://doi.org/10.3390/molecules24142529
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. https://doi.org/10.3390/molecules24142529
Chicago/Turabian StyleCerisier, Natacha, Michel Petitjean, Leslie Regad, Quentin Bayard, Manon Réau, Anne Badel, and Anne-Claude Camproux. 2019. "High Impact: The Role of Promiscuous Binding Sites in Polypharmacology" Molecules 24, no. 14: 2529. https://doi.org/10.3390/molecules24142529
APA StyleCerisier, N., Petitjean, M., Regad, L., Bayard, Q., Réau, M., Badel, A., & Camproux, A.-C. (2019). High Impact: The Role of Promiscuous Binding Sites in Polypharmacology. Molecules, 24(14), 2529. https://doi.org/10.3390/molecules24142529