The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures
Abstract
:1. Introduction
2. Results
2.1. Potential Binding Sites for Small Molecules
2.2. Verify the Accuracy of the Experimental Method Using MK-0893
2.3. Docking Situation of Five Small Molecules in Six Pockets
2.4. MD Simulation Was Used to Confirm Binding Modes of Small Molecules
2.5. Structural Modification Based on MD Results
3. Discussion
4. Materials and Methods
4.1. Homology Modeling
4.2. Molecular Dynamics Simulation
4.3. MDpocket Detects Pockets in MD Trajectories
4.4. Molecular Docking
4.5. Calculation and Decomposition the Binding Free Energy
4.6. Prediction of Pharmacokinetic Properties
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Molecule | Pocket 1 | Pocket 2 | Pocket 3 | Pocket 4 | Pocket 5 | Pocket 6 |
---|---|---|---|---|---|---|
Bay 27-9955 | −9.54 | −5.12 | −6.85 | −8.54 | ||
MK-3577 | −10.65 | −8.65 | −9.53 | −12.69 | −12.11 | −11.42 |
LY2409021 | −11.22 | −12.00 | −10.34 | −12.55 | −16.01 | −13.13 |
PF-06291874 | −11.06 | −12.05 | −9.26 | −8.18 | −10.75 | −11.54 |
LGD-6972 | −13.06 | −9.41 | −10.86 | −10.70 | −18.09 | −14.29 |
Molecule | Pocket 1 | Pocket 2 | Pocket 3 | Pocket 4 | Pocket 5 | Pocket 6 |
---|---|---|---|---|---|---|
Bay 27-9955 | −88.59 | −47.35 | −63.94 | −74.75 | ||
MK-3577 | −96.70 | −68.75 | −76.62 | −105.20 | −85.88 | −77.54 |
LY2409021 | −95.56 | −105.84 | −87.94 | −111.16 | −111.19 | −100.29 |
PF-06291874 | −85.33 | −85.62 | −73.21 | −57.33 | −81.46 | −72.30 |
LGD-6972 | −119.53 | −78.44 | −99.56 | −116.25 | −157.91 | −142.12 |
System | ΔGbind | ΔEvdw | ΔEele | ΔGpolar |
---|---|---|---|---|
Bay-1 | −19.43 | −44.65 | 29.89 | −4.67 |
Bay-2 | −29.21 | −40.75 | 16.07 | −4.53 |
Bay-3 | −28.12 | −42.34 | 18.79 | −4.57 |
Mean ± SD | −25.59 ± 3.09 | −42.58 ± 1.13 | 21.58 ± 4.23 | −4.59 ± 0.04 |
MK-1 | −31.97 | −25.69 | −2.69 | −3.60 |
MK-2 | −26.12 | −26.66 | 4.23 | −3.69 |
MK-3 | −31.06 | −27.62 | 0.17 | −3.62 |
Mean ± SD | −29.72 ± 1.82 | −26.66 ± 0.56 | 0.57 ± 2.01 | −3.64 ± 0.03 |
LY-1 | −43.87 | −39.36 | 0.32 | −4.83 |
LY-2 | −56.02 | −32.74 | −18.92 | −4.36 |
LY-3 | −43.66 | −40.11 | 1.24 | −4.79 |
Mean ± SD | −47.85 ± 4.09 | −37.40 ± 2.34 | −5.79 ± 6.57 | −4.66 ± 0.15 |
LY-p-1 | −29.15 | −43.42 | 19.68 | −5.41 |
LY-p-2 | −49.05 | −45.75 | 2.58 | −5.88 |
LY-p-3 | −26.13 | −38.82 | 18.01 | −5.31 |
Mean ± SD | −34.78 ± 7.19 | −42.66 ± 2.04 | 13.42 ± 5.44 | −5.53 ± 0.18 |
PF-1 | −33.10 | −35.68 | 6.86 | −4.28 |
PF-2 | −37.01 | −34.49 | 1.79 | −4.31 |
PF-3 | −25.17 | −24.52 | 2.65 | −3.29 |
Mean ± SD | −31.76 ± 3.48 | −31.56 ± 3.54 | 3.77 ± 1.57 | −3.96 ± 0.34 |
LGD-1 | −63.51 | −67.33 | 11.09 | −7.26 |
LGD-2 | −53.78 | −66.80 | 20.29 | −7.27 |
LGD-3 | −36.81 | −67.83 | 38.32 | −7.29 |
Mean ± SD | −51.37 ± 7.80 | −67.32 ± 0.30 | 23.23 ± 8.00 | −7.27 ± 0.01 |
Molecule | HBA (≤10) | HBD (≤5) | TPSA (Å2) | Synthetic Accessibility (0–10) |
---|---|---|---|---|
LGD-6972 | 5 | 3 | 120.95 | 5.19 |
Compound1 | 7 | 4 | 158.25 | 5.43 |
Compound2 | 6 | 4 | 141.18 | 5.24 |
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Wang, M.; Fu, X.; Du, L.; Shi, F.; Huang, Z.; Yang, L. The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures. Int. J. Mol. Sci. 2024, 25, 8389. https://doi.org/10.3390/ijms25158389
Wang M, Fu X, Du L, Shi F, Huang Z, Yang L. The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures. International Journal of Molecular Sciences. 2024; 25(15):8389. https://doi.org/10.3390/ijms25158389
Chicago/Turabian StyleWang, Mengru, Xulei Fu, Limin Du, Fan Shi, Zichong Huang, and Linlin Yang. 2024. "The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures" International Journal of Molecular Sciences 25, no. 15: 8389. https://doi.org/10.3390/ijms25158389