Exploring binding modes of the selected inhibitors to phosphodiesterase delta by all-atom molecular dynamics simulations and free energy calculations

Abstract

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

Keywords:

• KRas
• PDEδ
• inhibitor interaction mechanism
• molecular dynamic simulations
• MM-GB/SA

Acknowledgement

The authors thank Prof. Dr. Ju-Guang Han (University of Science and Technology of China) for his useful discussion and kind helps.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The present work is supported by National Natural Science foundation of China [11647002].