title: In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1.
abstract: BACKGROUND
  We use our earlier experimental studies of the catalytic mechanism of DNA methyltransferases to prepare in silico a family of novel mechanism-based inhibitors of human Dnmt1. Highly specific inhibitors of DNA methylation can be used for analysis of human epigenome and for the creation of iPS cells.
  
  
  RESULTS
  We describe a set of adenosyl-1-methyl-pyrimidin-2-one derivatives as novel mechanism-based inhibitors of mammalian DNA methyltransferase Dnmt1. The inhibitors have been designed to bind simultaneously in the active site and the cofactor site and thus act as transition-state analogues. Molecular dynamics studies showed that the lead compound can form between 6 to 9 binding interactions with Dnmt1. QM/MM analysis showed that the upon binding to Dnmt1 the inhibitor can form a covalent adduct with active site Cys1226 and thus act as a mechanism-based suicide-inhibitor. The inhibitor can target DNA-bond and DNA-free form of Dnmt1, however the suicide-inhibition step is more likely to happen when DNA is bound to Dnmt1. The validity of presented analysis is described in detail using 69 modifications in the lead compound structure. In total 18 of the presented 69 modifications can be used to prepare a family of highly specific inhibitors that can differentiate even between closely related enzymes such as Dnmt1 and Dnmt3a DNA methyltransferases.
  
  
  CONCLUSIONS
  Presented results can be used for preparation of some highly specific and potent inhibitors of mammalian DNA methylation with specific pharmacological properties.
authors.affiliation: Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies (HITS), University of Heidelberg, Heidelberg, Germany.
authors.forename: Vedran
authors.identifier: http://orcid.org/0000-0003-3981-8806
authors.initials: V
authors.lastname: Miletić
authors.affiliation: Laboratory for Biomolecular Structure and Function, Department of BioMedical Technology, Center for Advanced Computing and Modelling (CNRM), University of Rijeka, Rijeka, Croatia.
authors.forename: Ivica
authors.identifier: http://orcid.org/0000-0002-8121-3803
authors.initials: I
authors.lastname: Odorčić
authors.affiliation: Laboratory for Biomolecular Structure and Function, Department of BioMedical Technology, Center for Advanced Computing and Modelling (CNRM), University of Rijeka, Rijeka, Croatia.
authors.forename: Patrik
authors.initials: P
authors.lastname: Nikolić
authors.affiliation: Laboratory for Biomolecular Structure and Function, Department of BioMedical Technology, Center for Advanced Computing and Modelling (CNRM), University of Rijeka, Rijeka, Croatia.
authors.forename: Željko M
authors.identifier: http://orcid.org/0000-0002-0736-6182
authors.initials: ŽM
authors.lastname: Svedružić
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D004247:DNA / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011744:Pyrimidinones / Q000737:chemistry; D011789:Quantum Theory
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D000241:Adenosine