title: Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer.
abstract: DNA methyltransferases (DNMTs) is a key epigenetic enzyme for pharmacological manipulation and is employed in cancer reprogramming. During past few years multiple strategies have been implemented to excavate epigenetic compounds targeting DNMTs. In light of the emerging concept of chemoinformatics, molecular docking and simulation studies have been employed to accelerate the development of DNMT inhibitors. Among the DNMT inhibitors known till date, epigallocathechin-3-gallate (EGCG) was identified to be effective in reducing DNMT activity. However, the broad spectrum of EGCG to other diseases and variable target enzymes offers some limitations. In view of this, 32 EGCG analogues were screened at S-Adnosyl-L-homocysteine (SAH) binding pocket of DNMTs and procyanidin B2-3, 3'-di-O-gallate (procyanidin B2) was obtained as potent inhibitor having medicinally relevant chemical space. Further, in vitro analysis demonstrates the efficiency of procyanidin B2 in attenuating DNMT activity at IC50 of 6.88±0.647 μM and subsequently enhancing the expression of DNMT target genes, E-cadherin, Maspin and BRCA1. Moreover, the toxic property of procyanidin B2 towards triple negative breast cancer cells to normal cells offers platform for pre-clinical trial and an insight to the treatment of cancer.
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Arunima
authors.initials: A
authors.lastname: Shilpi
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Sabnam
authors.initials: S
authors.lastname: Parbin
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Dipta
authors.initials: D
authors.lastname: Sengupta
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Swayamsiddha
authors.initials: S
authors.lastname: Kar
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Moonmoon
authors.initials: M
authors.lastname: Deb
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Sandip Kumar
authors.initials: SK
authors.lastname: Rath
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Nibedita
authors.initials: N
authors.lastname: Pradhan
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Rakshit
authors.affiliation: Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India. Electronic address: samirp@nitrkl.ac.in.
authors.forename: Samir Kumar
authors.initials: SK
authors.lastname: Patra
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D044945:Proanthocyanidins / Q000494:pharmacology*; D016415:Sequence Alignment
chemical_list: D044946:Biflavonoids; D004791:Enzyme Inhibitors; D044945:Proanthocyanidins; C479580:procyanidin B2; D002392:Catechin; C045651:epigallocatechin gallate; D015254:DNA Modification Methylases
keywords: Cancer; DNA methyltransferases; DNMT activity assay; Molecular docking; Procyanidin B2; Simulation