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Title
Japanese:QUBO Problem Formulation of Fragment-Based Protein–Ligand Flexible Docking 
English:QUBO Problem Formulation of Fragment-Based Protein–Ligand Flexible Docking 
Author
Japanese: 柳澤渓甫, 藤江 拓哉, 高畠 和輝, 秋山 泰.  
English: Keisuke Yanagisawa, Takuya Fujie, Kazuki Takabatake, Yutaka Akiyama.  
Language English 
Journal/Book name
Japanese: 
English:Entropy 
Volume, Number, Page 26       
Published date Apr. 30, 2024 
Publisher
Japanese: 
English:MDPI 
Conference name
Japanese: 
English: 
Conference site
Japanese: 
English: 
Official URL https://doi.org/10.3390/e26050397
 
DOI https://doi.org/10.3390/e26050397
Abstract Protein–ligand docking plays a significant role in structure-based drug discovery. This methodology aims to estimate the binding mode and binding free energy between the drug-targeted protein and candidate chemical compounds, utilizing protein tertiary structure information. Reformulation of this docking as a quadratic unconstrained binary optimization (QUBO) problem to obtain solutions via quantum annealing has been attempted. However, previous studies did not consider the internal degrees of freedom of the compound that is mandatory and essential. In this study, we formulated fragment-based protein–ligand flexible docking, considering the internal degrees of freedom of the compound by focusing on fragments (rigid chemical substructures of compounds) as a QUBO problem. We introduced four factors essential for fragment–based docking in the Hamiltonian: (1) interaction energy between the target protein and each fragment, (2) clashes between fragments, (3) covalent bonds between fragments, and (4) the constraint that each fragment of the compound is selected for a single placement. We also implemented a proof-of-concept system and conducted redocking for the protein–compound complex structure of Aldose reductase (a drug target protein) using SQBM+, which is a simulated quantum annealer. The predicted binding pose reconstructed from the best solution was near-native (RMSD = 1.26 Å), which can be further improved (RMSD = 0.27 Å) using conventional energy minimization. The results indicate the validity of our QUBO problem formulation.

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