title: Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays.
abstract: DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy. In this study, structure-based virtual screening in combination with biological assays was performed to discovery potent novel DNMT3A inhibitors. Compound 40 and 40_3 displayed comparable in vitro inhibitory activity against DNMT3A with IC50values of 46.5μM and 41μM, respectively. Further binding mode analysis suggested these molecules inhibit DNMT3A activity through binding the S-adenosyl-l-methionine (SAM) pocket. Overall, 40 and 40_3 may serve as novel scaffolds for further optimization and small molecular probes for investigating DNMT3A function.
authors.affiliation: Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Xu
authors.affiliation: Obstetrics & Gynecology Hospital of Fudan University, No. 419 Fangxie Road, Shanghai 200011, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
authors.forename: Linjuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shien
authors.initials: S
authors.lastname: Liu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
authors.forename: Rukang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Shanghai ChemPartner Co., LTD, Building 5, 998, Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Shanghai ChemPartner Co., LTD, Building 5, 998, Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
authors.forename: Chenhua
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: shijiechen@simm.ac.cn.
authors.forename: Shijie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: cluo@simm.ac.cn.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C000717967:DNMT3A protein, human; D004791:Enzyme Inhibitors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNMT3A inhibitors; Epigenetics; Molecular docking; Virtual screening