A new method for estimating the relative binding free energy, derived from a free energy variational principle for the Pim-1-kinase-ligand and FKBP-ligand systems.

Abstract

In this study, a new method is proposed for calculating the relative binding free energy between a ligand and a protein, derived from a free energy variational principle (FEVP). To address the shortcomings of the method used in our previous study, we incorporate the dynamical fluctuation of a ligand in the FEVP calculation. The present modified method is applied to the Pim-1-kinase-ligand system and also to the FKBP-ligand system as a comparison with our previous work. Any inhibitor of Pim-1 kinase is expected to function as an anti-cancer drug. Some improvements are observed in the results compared to the previous study. The present work also shows comparable or better results than approaches using a standard technique of binding free energy calculations, such as the LIE and the MM-PB/SA methods. The possibility of applying the present method in the drug discovery process is also discussed.

• Authors: Takeshi Ashida, Takeshi Kikuchi
• Journal: Journal of computer-aided molecular design (J Comput Aided Mol Des) Vol. 34 Issue 6 Pg. 647-658 (06 2020) ISSN: 1573-4951 [Electronic] Netherlands
• PMID: 32107701 (Publication Type: Journal Article)

Chemical References

• Ligands
• Proto-Oncogene Proteins c-pim-1
• Tacrolimus Binding Proteins

Topics

• Energy Metabolism
• Entropy
• Humans
• Ligands
• Molecular Dynamics Simulation
• Protein Binding (genetics)
• Protein Conformation
• Proto-Oncogene Proteins c-pim-1 (chemistry)
• Tacrolimus Binding Proteins (chemistry)
• Thermodynamics