Paper Info
Title
Binding Thermodynamics And Interaction Patterns Of Human Purine Nucleoside Phosphorylase-Inhibitor Complexes From Extensive Free Energy Calculations
Abstract
Human purine nucleoside phosphorylase (hPNP) plays a significant role in the catabolism of deoxyguanosine. The trimeric protein is an important target in the treatment of T-cell cancers and autoimmune disorders. Experimental studies on the inhibition of the hPNP observe that the first ligand bound to one of three subunits effectively inhibits the protein, while the binding of more ligands to the subsequent sites shows negative cooperativities. In this work, we performed extensive end-point and alchemical free energy calculations to determine the binding thermodynamics of the trimeric protein-ligand system. 13 Immucillin inhibitors with experimental results are under calculation. Two widely accepted charge schemes for small molecules including AM1-BCC and RESP are adopted for ligands. The results of RESP are in better agreement with the experimental reference. Further investigations of the interaction networks in the protein-ligand complexes reveal that several residues play significant roles in stabilizing the complex structure. The most commonly observed ones include PHE200, GLU201, MET219, and ASN243. The conformations of the protein in different protein-ligand complexes are observed to be similar. We expect these insights to aid the development of potent drugs targeting hPNP.
Year
DOI
Venue
2021
10.1007/s10822-021-00382-w
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Keywords
DocType
Volume
Binding free energy, Protein&#8211, ligand interaction, Benchmarking force fields, Alchemical free energy calculation, End-point free energy methods
Journal
35
Issue
ISSN
Citations 
5
0920-654X
1
PageRank 
References 
Authors
0.35
0
3
Name
Order
Citations
PageRank
Zhe Huai110.69
Huaiyu Yang210.69
Zhaoxi Sun310.69