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Understanding PIM-1 kinase inhibitor interactions with free energy simulation
- Source :
- Physical Chemistry Chemical Physics. 21:7544-7558
- Publication Year :
- 2019
- Publisher :
- Royal Society of Chemistry (RSC), 2019.
-
Abstract
- The proviral integration site of the Moloney leukemia virus (PIM) family includes three homologous members. PIM-1 kinase is an important target in effective therapeutic interventions of lymphomas, prostate cancer and leukemia. In the current work, we performed free energy calculations to calculate the binding affinities of several inhibitors targeting this protein. The alchemical method with integration and perturbation-based estimators and the end-point methods were compared. The computational results indicated that the alchemical method can accurately predict the binding affinities, while the end-point methods give relatively unreliable predictions. Decomposing the free energy difference into enthalpic and entropic components with MBAR reweighting enabled us to investigate the detailed thermodynamic parameters with which the entropy-enthalpy compensation in this protein-ligand binding case is identified. We then studied the conformational ensemble, and the important protein-ligand interactions were identified. The current work sheds light on the understanding of the PIM-1-kinase-inhibitor interactions at the atomic level and will be useful in the further development of potential drugs.
- Subjects :
- Proviral integration
General Physics and Astronomy
02 engineering and technology
Computational biology
Plasma protein binding
Molecular Dynamics Simulation
Ligands
010402 general chemistry
01 natural sciences
Molecular dynamics
Proto-Oncogene Proteins c-pim-1
hemic and lymphatic diseases
Humans
Physical and Theoretical Chemistry
Binding site
Energy simulation
Protein Kinase Inhibitors
Moloney leukemia virus
Binding affinities
Binding Sites
Chemistry
Pim-1 Kinase
021001 nanoscience & nanotechnology
0104 chemical sciences
Quantum Theory
Thermodynamics
0210 nano-technology
Protein Binding
Subjects
Details
- ISSN :
- 14639084 and 14639076
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Physical Chemistry Chemical Physics
- Accession number :
- edsair.doi.dedup.....1b8735eef49af07f69e5c1fbc725135a