A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods
Abstract
:1. Introduction
1.1. Dopamine Receptors
1.2. Computer-Aided Drug Design
1.3. Aim
2. Results
2.1. Homology Models of Dopamine Receptors D1R-D5R Are Stable
2.2. Dopamine Receptor Binding Pocket Definition
2.3. Proof-of-Concept of Molecular Docking Success
2.4. Docking of Various Ligands to DR Models
2.5. The Type of Pairwise Interactions Between Receptor Amino-Acids and Ligand is Relevant for Binding
2.6. 2.5 Å-Interactions
2.7. Hydrogen Bonds and Hydrophobic Contacts
2.8. Salt-Bridges
2.9. Cat-π- and π-π-Stacking Interactions
2.10. T-Stacking Interactions
3. Discussion
3.1. Validation of the In Silico Pipeline
3.2. Pairwise Interactions Analysis Was Able to Determine Key Amino-Acids and Types of Interaction
4. Materials and Methods
4.1. Homology Modeling
4.1.1. General Approach
4.1.2. Model Evaluation/Methods of Quality
4.2. Molecular Dynamics
4.2.1. System Setup
4.2.2. Molecular Dynamics Simulation Protocol
4.3. Molecular Docking
4.3.1. Ligand Dataset
4.3.2. Docking Procedure
4.3.3. Analysis of Molecular Docking
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
LIGAND | FUNCTION | BP | REFERENCES | |
---|---|---|---|---|
DOPAMINE | Endogenous agonist of all DR | OBP | [47,52,65] | |
7-OH-DPAT | Synthetic D3R selective agonist | OBP | [47,65,66] | |
APOMORPHINE | D2R selective agonist | OBP | [47,52,65] | |
BROMOCRIPTINE | D2R selective agonist | OBP | [47,65] | |
CLOZAPINE | “Dirty drug”, multiple receptor binding | OBP | [47,65,67,68] | |
NEMONAPRIDE | D2R/D3R selective antagonist | OBP + SBP | [38,47,55,65] | |
SULPIRIDE | “Dirty drug”, multiple receptor binding | OBP + SBP | [47,65,66] | |
SCH23390 | D1R antagonist | OBP | [31,47,65,69] | |
SKF38393 | D1R selective agonist | OBP | [31,47,65,70] | |
ETICLOPRIDE | D2R/D3R selective antagonist | OBP + SBP | [37,66] | |
RISPERIDONE | “Dirty drug”, multiple receptor binding | OBP+SBP | [36,47] | |
ARIPIPRAZOLE | Partial D2R agonist, D2R/D3R heterodimer antagonist | OBP + SBP | [66,71] | |
HALOPERIDOLE | D2R selective antagonist, D4R antagonist | OBP+SBP | [47,65,67,72,73] | |
SPIPERONE | Affinity for all DR | OBP + SBP | [47,65,66] | |
CHLORPROMAZINE | Antagonist on all DR | OBP | [47,65,74] |
DOPAMINE RECEPTOR | TEMPLATE | BLAST [%] | CLUSTALOMEGA [%] |
---|---|---|---|
D1R | 3PBL | 35.0 | 39.5 |
D2R | 6CM4 | 97.0 | 100.0 |
D3R | 3PBL | 93.0 | 99.3 |
D4R | 5WIU | 93.0 | 100.0 |
D5R | 5WIU | 35.0 | 39.1 |
DR | DOPE | LGscore | LGscore + PSIPRED | MaxSub | MaxSub + PSIPRED | z-Score |
---|---|---|---|---|---|---|
D1R | −39070.82 | 2.53 | 4.26 | 0.18 | 0.53 | −2.14 |
D2R | −39284.66 | 2.52 | 4.22 | 0.21 | 0.52 | −2.22 |
D3R | −39458.37 | 3.14 | 4.19 | 0.27 | 0.55 | −3.12 |
D4R | −36738.05 | 3.33 | 4.25 | 0.25 | 0.59 | −3.90 |
D5R | −38356.05 | 2.60 | 4.14 | 0.15 | 0.57 | −1.49 |
LIGAND | FLEXIBLE RESIDUES IN B&W NUMBERING |
---|---|
DOPAMINE | 3.32Asp, 5.42Ser, 5.43Ser, 5.46Ser, 6.48Trp, 6.51Phe, 6.52Phe, 6.55His/Asn |
7-OH-DPAT | |
APOMORPHINE | 3.32Asp, 3.36/3.35Cys, 5.42Ser, 5.43Ser, 5.46Ser, 6.48Trp, 6.51Phe, 6.52Phe, 6.55His/Asn |
BROMOCRIPTINE | |
CLOZAPINE | 3.32Asp, 3.33Val, 3.36Cys, 5.42Ser, 5.43Ser, 5.46Ser, 6.48Trp, 6.55His/Asn |
NEMONAPRIDE | 2.57Val, 3.32Asp, 5.42Ser, 5.43Ser, 5.46Ser, 6.48Trp, 6.51Phe, 6.52Phe, 7.43Tyr |
SULPIRIDE | 3.32Asp, 6.48Trp, 5.42Ser, 5.43Ser, 5.46Ser, 6.55His/Asn, 7.43Tyr, 6.51Phe |
SCH23390 | 3.32Asp, 6.48Trp, 5.42Ser, 5.43Ser, 5.46Ser, 6.55His/Asn, 6.51Phe, 6.52Phe |
SKF38393 | |
ETICLOPRIDE | 3.32Asp, 6.48Trp, 5.42Ser, 5.43Ser, 5.46Ser, 6.55His/Asn, 7.43Tyr, 6.51Phe, 6.52Phe |
RISPERIDONE | 3.32Asp, 6.48Trp, 3.36Cys, 6.55His/Asn, 2.57Val, 5.42Ser, 5.43Ser, 5.46Ser |
ARIPIPRAZOLE | 3.32Asp, 6.48Trp, 3.33Val, 5.42Ser, 5.43Ser, 5.46Ser, 7.43Tyr, 6.55His/Asn |
HALOPERIDOLE | 3.32Asp, 6.48Trp, 6.51Phe, 6.52Phe, 3.36Cys, 2.57Val, 5.42Ser, 5.43Ser, 5.46Ser |
SPIPERONE | 3.32Asp, 6.48Trp, 5.42Ser, 5.43Ser, 5.46Ser, 3.36Cys, 6.55His/Asn, 2.57Val |
CHLORPROMAZINE | 3.32Asp, 6.48Trp, 5.42Ser, 5.43Ser, 5.46Ser, 6.55His/Asn, 3.36Cys, 6.51Phe |
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Bueschbell, B.; Barreto, C.A.V.; Preto, A.J.; Schiedel, A.C.; Moreira, I.S. A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods. Molecules 2019, 24, 1196. https://doi.org/10.3390/molecules24071196
Bueschbell B, Barreto CAV, Preto AJ, Schiedel AC, Moreira IS. A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods. Molecules. 2019; 24(7):1196. https://doi.org/10.3390/molecules24071196
Chicago/Turabian StyleBueschbell, Beatriz, Carlos A. V. Barreto, António J. Preto, Anke C. Schiedel, and Irina S. Moreira. 2019. "A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods" Molecules 24, no. 7: 1196. https://doi.org/10.3390/molecules24071196
APA StyleBueschbell, B., Barreto, C. A. V., Preto, A. J., Schiedel, A. C., & Moreira, I. S. (2019). A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods. Molecules, 24(7), 1196. https://doi.org/10.3390/molecules24071196