Exploring binding modes of the selected inhibitors to phosphodiesterase delta by all-atom molecular dynamics simulations and free energy calculations
| Autor: | Yan-Jun Zhang, Xiao-Bin Shan, Hui Zhong |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Stereochemistry
Phosphodiesterase Inhibitors 030303 biophysics Binding energy Molecular Dynamics Simulation Affinity binding 03 medical and health sciences symbols.namesake Molecular dynamics chemistry.chemical_compound Protein Domains Structural Biology Atom Molecular Biology 0303 health sciences Binding Sites Chemistry Hydrogen bond Phosphoric Diester Hydrolases Phosphodiesterase Hydrogen Bonding General Medicine Molecular Docking Simulation Protein Subunits Pyrazines symbols Pyrazoles Thermodynamics Benzimidazoles van der Waals force Derivative (chemistry) Protein Binding |
| Zdroj: | Journal of biomolecular structuredynamics. 37(9) |
| ISSN: | 1538-0254 |
| Popis: | It's favorable to alter KRas mutation's location to endomembrane by interfering the binding of PDEδ (the prenyl-binding protein phosphodiesterase delta) to KRas. In the present work, the binding of four inhibitors (Deltarasin, allyl analogue, pyrazolopyridazinone derivative, and Deltazinone 1) to PDEδ is investigated with all-atom Molecular Dynamic (MD) simulations. The binding free energy calculation results reveal that van der Waals (VDW) energy provides the major force for affinity binding. Moreover, the binding energy decomposition indicates that residues R61 and I129 provide important contributions to binding energies in all systems. The conserved hydrogen bonds play crucial roles in anchoring the inhibitors to the exact site for binding. The results for conformational analysis of PDEδ/free and PDEδ/inhibitors systems show that the structures are more stable after the inhibitors' binding to the PDEδ. It is also found that the most unstable system among four complexes is PDEδ/pyrazolopyridazinone derivative system whose α3-helix formed by the residues P113-Q116 disappears. This study may provide valuable information for the design of high potency PDEδ inhibitors. Communicated by Ramaswamy H. Sarma. |
| Databáze: | OpenAIRE |
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