Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Molecular Modeling of Pim3
2.2. Overall Structure and Dynamics
2.3. Binding Free Energies Estimated by MM/GBSA
2.4. Decomposition Analysis of the Binding Free Energies
3. Materials and Methods
3.1. Homology Model of Pim3
3.2. Optimization of Homology Model of Pim3
3.3. Construction of Six Pim/Ligand Systems
3.4. Molecular Dynamics Simulations
3.5. MM/GBSA Calculation and MM/GBSA Free Energy Decomposition Analysis
= ΔEMM + ΔGGB + ΔGSA − TΔS
= ΔEvdw + ΔEele + ΔGGB + ΔGSA − TΔS
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Pim | proviral integration site of the Moloney murine leukemia virus |
MD | molecular dynamics |
MM/GBSA | molecular mechanics generalized Born/surface area |
References
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Models | molpdf a | DOPE Score b | GA341 Score c |
---|---|---|---|
Pim3.B99990001 | 1709.42212 | −33,078.14063 | 1.00000 |
Pim3.B99990002 | 1679.96997 | −33,142.85938 | 1.00000 |
Pim3.B99990003 | 1775.07397 | −33,461.44922 | 1.00000 |
Pim3.B99990004 | 1816.04749 | −33,243.78516 | 1.00000 |
Pim3.B99990005 | 1728.24146 | −33,196.65234 | 1.00000 |
System | ΔEvdw | ΔEele | ΔGGB | ΔGSA | TΔS | ΔGbind | Ki (pM) |
---|---|---|---|---|---|---|---|
Pim1/AZD1208 | −39.65 ± 3.16 | −5.45 ± 3.33 | 9.39 ± 1.99 | −5.90 ± 0.18 | −10.44 ± 2.28 | −31.17 ± 2.64 | 17 |
Pim1/PIM447 | −47.98 ± 2.68 | −9.99 ± 2.56 | 15.94 ± 2.16 | −6.36 ± 0.17 | −11.24 ± 2.71 | −37.15 ± 2.46 | 6 |
Pim2/AZD1208 | −37.27 ± 2.98 | −6.16 ± 3.02 | 10.83 ± 2.38 | −5.92 ± 0.19 | −13.33 ± 2.14 | −25.19 ± 2.67 | 160 |
Pim2/PIM447 | −46.81 ± 3.00 | −10.69 ± 2.27 | 15.86 ± 1.78 | −6.38 ± 0.12 | −12.10 ± 2.45 | −35.92 ± 2.88 | 18 |
Pim3/AZD1208 | −39.24 ± 3.21 | −9.55 ± 2.50 | 12.61 ± 1.87 | −5.90 ± 0.13 | −13.47 ± 2.63 | −28.61 ± 2.95 | 230 |
Pim3/PIM447 | −49.55 ± 2.33 | −9.41 ± 1.59 | 15.76 ± 1.17 | −6.63 ± 0.11 | −11.26 ± 2.36 | −38.58 ± 2.19 | 9 |
System | Top | Bottom | Right | Left | Loop | Sum |
---|---|---|---|---|---|---|
Pim1/PIM447 | −7.49 | −3.93 | −3.51 | −2.87 | −2.26 | −20.06 |
Pim2/PIM447 | −6.79 | −3.83 | −3.77 | −2.65 | −1.68 | −18.72 |
Pim3/PIM447 | −7.97 | −4.67 | −4.20 | −2.01 | −0.81 | −19.66 |
Pim1/AZD1208 | −7.01 | −1.50 | −4.00 | −2.77 | −2.38 | −17.66 |
Pim2/AZD1208 | −6.61 | −1.87 | −4.38 | −2.77 | −0.05 | −15.68 |
Pim3/AZD1208 | −6.21 | −1.86 | −4.03 | −2.61 | −2.47 | −17.18 |
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Chen, Q.; Wang, Y.; Shi, S.; Li, K.; Zhang, L.; Gao, J. Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study. Int. J. Mol. Sci. 2019, 20, 5410. https://doi.org/10.3390/ijms20215410
Chen Q, Wang Y, Shi S, Li K, Zhang L, Gao J. Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study. International Journal of Molecular Sciences. 2019; 20(21):5410. https://doi.org/10.3390/ijms20215410
Chicago/Turabian StyleChen, Qingqing, Yan Wang, Shanshan Shi, Kaihang Li, Ling Zhang, and Jian Gao. 2019. "Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study" International Journal of Molecular Sciences 20, no. 21: 5410. https://doi.org/10.3390/ijms20215410