Docking, Binding Free Energy Calculations and In Vitro Characterization of Pyrazine Linked 2-Aminobenzamides as Novel Class I Histone Deacetylase (HDAC) Inhibitors
Abstract
:1. Introduction
2. Results
2.1. Diversity Analysis of Studied Dataset
2.2. Analysis of Protein-Inhibitor Complexes
2.3. Docking Results of the Training Set
2.4. Rescoring of Docking Poses Using MM-GB/SA and MM-PB/SA
2.5. Evaluation of Novel Designed HDAC1-2-3 Inhibitors
3. Discussion
4. Materials and Methods
4.1. Training Set and Diversity Analysis
4.2. Preparation of Protein-Inhibitor Complexes
4.3. Molecular Docking
4.4. Molecular Dynamics (MD) Simulations
4.5. Binding Free Energy (BFE) Calculations
4.6. Test Set
4.7. Experimental Data of the Synthesized Compounds
4.8. Biological Assay of the Synthesized Compounds
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Cpd. No. | Substituents | IC50 (µM) or % Inhibition at Given Concentration | ||||||
---|---|---|---|---|---|---|---|---|
X | Y | R1 | R2 | R3 | HDAC1 | HDAC2 | HDAC3 | |
19a | CH | N | H | H | 0.51 ± 0.05 | 0.80 ± 0.07 | 1.12 ± 0.07 | |
19b | CH | N | H | H | 26% @ 2 µM | 30% @ 2 µM | 65% @ 2 µM | |
19c | N | CH | H | H | 34% @ 2 µM | 20% @ 2 µM | 27% @ 2 µM | |
19d | CH | N | H | H | 0.52 ± 0.07 | 1.43 ± 0.08 | 1.06 ± 0.04 | |
19e | CH | N | H | H | 0.21 ± 0.07 | 0.71 ± 0.04 | 0.84 ± 0.03 | |
19f | CH | N | H | H | 0.13 ± 0.01 | 0.28 ± 0.01 | 0.31 ± 0.01 | |
19g | CH | N | H | H | 0.31 ± 0.03 | 0.96 ± 0.05 | 0.49 ± 0.06 | |
19h | CH | N | F | F | 0.81 ± 0.07 | 0.74 ± 0.03 | 0.57 ± 0.02 | |
19i | CH | N | Cl | H | 3.0 ± 0.2 | 2.7 ± 0.2 | 1.9 ± 0.1 | |
19j | N | CH | H | H | 0.45 ± 0.06 | 0.93 ± 0.04 | 1.75 ± 0.06 | |
19k | CH | N | H | H | 0.14 ± 0.02 | 0.56 ± 0.04 | 0.59 ± 0.03 | |
19l | CH | N | F | F | 0.29 ± 0.03 | 0.56 ± 0.02 | 0.81 ± 0.05 | |
19m | CH | N | F | H | 0.40 ± 0.06 | 1.48 ± 0.19 | 0.40 ± 0.02 | |
19n | N | CH | CH3 | H | H | 5% @ 1 µM | 7% @ 1 µM | 13% @ 1 µM |
19o | CH | N | CH3 | H | H | 27% @ 1 µM | 15% @ 1 µM | 30% @ 1 µM |
21a | CH | N | H | 2-Thienyl | 0.26 ± 0.01 | 2.47 ± 0.22 | 0% @ 1 µM | |
21b | CH | N | H | 4-F-C6H4 | 0.70 ± 0.08 | 0.77 ± 0.06 | 0% @ 1 µM | |
21c | CH | N | H | 2-F-C6H4 | 0.76 ± 0.07 | 0.76 ± 0.04 | 15 ± 1 | |
23a | CH | N | H | F | H | 3.30 ± 0.18 | 2.17 ± 0.18 | 0.40 ± 0.01 |
23b | CH | N | H | F | 0.27 ± 0.03 | 0.50 ± 0.03 | 0.50 ± 0.02 | |
23c | CH | N | H | F | 0.33 ± 0.02 | 1.37 ± 0.08 | 0.59 ± 0.04 | |
25a | CH | N | H | Cl | H | 0% @ 1 µM | 0% @ 1 µM | 8.7 ± 0.4 |
25b | CH | N | H | F | F | 4.3 ± 0.3 | 4.2 ± 0.15 | 1.6 ± 0.1 |
27a | CH | N | H | H | CF3 | 0% @ 1 µM | 0% @ 1 µM | 0% @ 1 µM |
27b | CH | N | H | CH3 | H | 0% @ 1 µM | 0% @ 1 µM | 0% @ 1 µM |
27c | CH | N | H | OCH3 | H | 20.0 ± 1.0 | 14.0 ± 2.0 | 14.0 ± 1.0 |
29a | CH | N | CH3 | H | 3-Thienyl | 0.11 ± 0.01 | 0.18 ± 0.06 | 4.4 ± 0.1 |
29b | CH | N | H | H | 2-Thienyl | 0.07 ± 0.01 | 0.26 ± 0.01 | 6.1 ± 0.7 |
29c | CH | N | H | H | 4-F-C6H4 | 0.16 ± 0.03 | 0.34 ± 0.01 | 6.7 ± 0.5 |
29d | CH | N | CH3 | H | 2-F-C6H4 | 0.18 ± 0.01 | 0.26 ± 0.07 | 12.0 ± 1.0 |
CI994 | -- | -- | -- | -- | -- | 37% @ 1 µM | 36% @ 1 µM | 32% @ 1 µM |
RGFP-966 | -- | -- | -- | -- | -- | 16 ± 2 | 11 ± 1 | 1.3 ± 0.1 |
MS-275 | -- | -- | -- | -- | -- | 0.93 ± 0.1 | 0.95 ± 0.03 | 1.8 ± 0.1 |
Mocetinostat | -- | -- | -- | -- | -- | 0.33 ± 0.04 | 0.34 ± 0.01 | 0.93 ± 0.05 |
Protein | N | Model Number | Solvation Model | Frame | R2 | RMSE | Q2LOO | QMSE |
---|---|---|---|---|---|---|---|---|
HDAC1 | 22 | 3 | GB1 | MD1-50 | 0.59 | 0.29 | 0.51 | 0.32 |
HDAC2 | 23 | 21 | GB8 | MD1-50 | 0.66 | 0.24 | 0.60 | 0.26 |
HDAC3 | 22 | 7 | GB2 | Emin1 | 0.71 | 0.29 | 0.65 | 0.32 |
Cpd. No. | Scaffold | Substituents | ||||
---|---|---|---|---|---|---|
X | Y | R1 | R2 | R3 | ||
30a | A | N | CH | −CH3 | H | 2-Thienyl |
30b | A | CH | N | −CH3 | H | 2-Thienyl |
30c | A | CH | N | H | 2-Thienyl | |
30d | A | CH | N | H | H | |
31a | B | CH | CH | F | H | |
31b | B | CH | CH | F | H | |
31c | B | CH | CH | F | H |
Cpd. No. | Scaffold | Experimental HDAC1 pIC50 | Predicted HDAC1 pIC50) | Difference Experimental—Predicted HDAC1 pIC50 | Experimental HDAC2 pIC50 | Predicted HDAC2 pIC50 | Difference Experimental—Predicted HDAC2 pIC50 | Experimental HDAC3 pIC50 | Predicted HDAC3 pIC50 |
---|---|---|---|---|---|---|---|---|---|
30a | A | 6.49 | 6.55 | 0.06 | 6.21 | 6.00 | 0.21 | 8% @1 µM 38% @10 μM | 5.06 |
30b | A | 7.40 | 6.31 | 1.09 | 6.10 | 6.24 | 0.14 | 6% @1 µM 35% @10 μM | 5.01 |
30c | A | 7.72 | 6.50 | 1.22 | 5.96 | 5.95 | 0.01 | 4% @1 µM 30% @10 μM | 4.98 |
30d | A | 5.72 | 5.70 | 0.02 | 4.62 | 5.89 | 1.27 | 15% @1 µM 72% @10 μM | 5.98 |
31a | B | 4% @1 µM 31% @10 µM | 5.58 | 10% @1 µM 37% @10 µM | 5.52 | 21% @1 µM 65% @10 µM | 5.81 | ||
31b | B | 0% @1 µM 27% @10 µM | 5.77 | 13% @1 µM 30% @10 µM | 5.29 | 19% @1 µM 59% @10 µM | 5.80 | ||
31c | B | 6% @1 µM 36% @10 µM | 5.68 | 14% @1 µM 51% @10 µM | 5.52 | 25% @1 µM 66% @10 µM | 5.79 |
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Bülbül, E.F.; Melesina, J.; Ibrahim, H.S.; Abdelsalam, M.; Vecchio, A.; Robaa, D.; Zessin, M.; Schutkowski, M.; Sippl, W. Docking, Binding Free Energy Calculations and In Vitro Characterization of Pyrazine Linked 2-Aminobenzamides as Novel Class I Histone Deacetylase (HDAC) Inhibitors. Molecules 2022, 27, 2526. https://doi.org/10.3390/molecules27082526
Bülbül EF, Melesina J, Ibrahim HS, Abdelsalam M, Vecchio A, Robaa D, Zessin M, Schutkowski M, Sippl W. Docking, Binding Free Energy Calculations and In Vitro Characterization of Pyrazine Linked 2-Aminobenzamides as Novel Class I Histone Deacetylase (HDAC) Inhibitors. Molecules. 2022; 27(8):2526. https://doi.org/10.3390/molecules27082526
Chicago/Turabian StyleBülbül, Emre F., Jelena Melesina, Hany S. Ibrahim, Mohamed Abdelsalam, Anita Vecchio, Dina Robaa, Matthes Zessin, Mike Schutkowski, and Wolfgang Sippl. 2022. "Docking, Binding Free Energy Calculations and In Vitro Characterization of Pyrazine Linked 2-Aminobenzamides as Novel Class I Histone Deacetylase (HDAC) Inhibitors" Molecules 27, no. 8: 2526. https://doi.org/10.3390/molecules27082526