title: The discovery of novel histone lysine methyltransferase G9a inhibitors (part 1): molecular design based on a series of substituted 2,4-diamino-7- aminoalkoxyquinazoline by molecular-docking-guided 3D quantitative structure-activity relationship studies.
abstract: Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. This suggests that small molecular inhibitors of G9a might be attractive antitumor agents. Herein we report our efforts on the design of novel G9a inhibitor based on the 3D quantitative structure-activity relationship (3D-QSAR) analysis of a series of 2,4-diamino-7-aminoalkoxyquinazolineas G9a inhibitors. The 3D-QSAR model was generated from 47 compounds using docking based molecular alignment. The best predictions were obtained with CoMFA standard model (q2 =0.700, r2 = 0.952) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q2 = 0.724, r2 =0.960). The structural requirements for substituted 2,4-diamino-7-aminoalkoxyquinazoline for G9a inhibitory activity can be obtained by analysing the COMSIA plots. Based on the information, six novel follow-up analogs were designed.
authors.forename: Taotao
authors.initials: T
authors.lastname: Feng
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Zhang
authors.forename: Haopeng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China. sunhaopeng@163.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D011495:Histone-Lysine N-Methyltransferase