title: Application of the fragment molecular orbital method analysis to fragment-based drug discovery of BET (bromodomain and extra-terminal proteins) inhibitors.
abstract: The molecular interactions of inhibitors of bromodomains (BRDs) were investigated. BRDs are protein interaction modules that recognizing ε-N-acetyl-lysine (εAc-Lys) motifs found in histone tails and are promising protein-protein interaction (PPI) targets. First, we analyzed a peptide ligand containing εAc-Lys to evaluate native PPIs. We then analyzed tetrahydroquinazoline-6-yl-benzensulfonamide derivatives found by fragment-based drug design (FBDD) and examined their interactions with the protein compared with the peptide ligand in terms of the inter-fragment interaction energy. In addition, we analyzed benzodiazepine derivatives that are high-affinity ligands for BRDs and examined differences in the CH/π interactions of the amino acid residues. We further surveyed changes in the charges of the amino acid residues among individual ligands, performed pair interaction energy decomposition analysis and estimated the water profile within the ligand binding site. Thus, useful insights for drug design were provided. Through these analyses and considerations, we show that the FMO method is a useful drug design tool to evaluate the process of FBDD and to explore PPI inhibitors.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan. Electronic address: motoyasu_ozawa@pharm.kissei.co.jp.
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Ozawa
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Graduate School of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-Ku, Yokohama 240-8501, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ueda
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D011789:Quantum Theory; D011799:Quinazolines / Q000737:chemistry*; D013816:Thermodynamics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D008024:Ligands; D009687:Nuclear Proteins; D011799:Quinazolines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Bromodomain inhibitor; CH/π interaction; FBDD; FMO; PPIs