Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 3, 2010, Pages 1124-1127

  Suzuki, Takayoshi ^a   Tanaka, Rikako ^a   Hamada, Shohei ^a   Nakagawa, Hidehiko ^a   Miyata, Naoki ^a  

^a NAGOYA CITY UNIVERSITY   (Japan)

Author keywords

DNA methyltransferase; Inhibitor; Non nucleoside

Indexed keywords

DNA METHYLTRANSFERASE 1 INHIBITOR; DNA METHYLTRANSFERASE INHIBITOR; MALEIMIDE DERIVATIVE; N PHTHALOYLTRYPTOPHAN; PHTHALIMIDE DERIVATIVE; UNCLASSIFIED DRUG; DNA (CYTOSINE 5) METHYLTRANSFERASE; DNA (CYTOSINE-5-)-METHYLTRANSFERASE 1; INDOLE DERIVATIVE; PROPIONIC ACID DERIVATIVE; PROTEIN BINDING; TRYPTOPHAN;

ARTICLE; CONTROLLED STUDY; DNA METHYLATION; DRUG BINDING; DRUG DESIGN; DRUG INHIBITION; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; IN VITRO STUDY; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; CHEMISTRY; COMPARATIVE STUDY; METABOLISM; PHYSIOLOGY; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

CRYSTALLOGRAPHY, X-RAY; DNA (CYTOSINE-5-)-METHYLTRANSFERASE; DRUG DESIGN; HUMANS; INDOLES; MALEIMIDES; PHTHALIMIDES; PROPIONATES; PROTEIN BINDING; TRYPTOPHAN;

EID: 74049094114     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.12.016     Document Type: Article

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26. For the in vitro methylation assay, EpiQuik™ DNA Methyltransferase Activity/Inhibitor Assay Kit (Epigentek Group Inc., Brooklyn, NY, USA) and human DNA (cytosine-5) methyltransferase (DNMT1) (New England Biolabs, Inc., Bevery, MA, USA) were used. Test samples were dissolved in DMSO and the solution was diluted by adding 10 parts of PBS. To the DHMT assay buffer in 0.5 mL tubes were added 1.6 mM S-adenosyl-l-methionine (AdoMet) and inhibitor solution. Then, DNMT1 was added to the tubes. The reaction mixture was mixed, transferred to the substrate DNA-coated strip wells, and incubated at 37 °C for 60 min. The reaction solution was discarded, methylation DNA capture antibody was added to the strip wells, and the mixture was incubated at room temperature for 60 min. After the capture antibody was aspirated, the detection antibody was added to the strip wells and incubation was carried out at room temperature for 30 min. Then, the antibody was removed, the developing solution was added to the strip wells, and incubation was carried out at room temperature for 10 min. Thereafter, the stop solution was added to the strip wells. The resultant mixture was transferred to a 96-well plate and absorbance at 450 nm was measured.
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28. The X-ray structure of M.Hha I{cyrillic, ukrainian} (PDB code 1M0E) was used as the target structure for docking. Protein preparation, receptor grid generation, and ligand docking were performed using the software Glide 3.5. Compound 5 was docked into the DNA binding site of M.Hha I{cyrillic, ukrainian}. The standard precision mode of Glide was used to determine favorable binding poses, which allowed the ligand conformation to be flexibly explored while holding the protein as a rigid structure during docking. Then, the predicted complex structure was fully energy-minimized with both the protein and the ligand allowed to move using Macromodel 8.1 software. The conformation of compound 5 in the DNA binding site was minimized by MM calculation based on the OPLS-AA force field with the following parameter set: solvent: water; method: LBFGS; max # of iterations: 10,000; converge: gradient; convergence threshold: 0.05.