title: Identifying novel selective non-nucleoside DNA methyltransferase 1 inhibitors through docking-based virtual screening.
abstract: The DNA methyltransferases (DNMTs) found in mammals include DNMT1, DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy. DNMT1 was the first among the DNMTs to be characterized, and it is responsible for maintaining DNA methylation patterns. A number of DNMT inhibitors have been reported, but most of them are nucleoside analogs that can lead to toxic side effects and lack specificity. By combining docking-based virtual screening with biochemical analyses, we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases. Through a process of similarity-based analog searching, compounds DC_501 and DC_517 were found to be more potent than DC_05. These three potent compounds significantly inhibited cancer cell proliferation. The structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Shijie
authors.initials: S
authors.lastname: Chen
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.forename: Jianlong
authors.initials: J
authors.lastname: Peng
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.forename: Junchi
authors.initials: J
authors.lastname: Hu
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Yijyun
authors.initials: Y
authors.lastname: Lin
authors.forename: Linjuan
authors.initials: L
authors.lastname: Li
authors.forename: Sufang
authors.initials: S
authors.lastname: Cheng
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D044127:Epigenesis, Genetic; D006801:Humans; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human