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Medicinal Chemistry
ISSN (Print): 1573-4064
ISSN (Online): 1875-6638
Epub Full Text Article
DOI: 10.2174/15734064113096660068      Price:  $95









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

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Author(s): Taotao Feng, Hai Wang, Xiaojin Zhang, Haopeng Sun and Qidong You
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
Keywords:
CoMSIA, G9a inhibitors, molecular modeling, novel compounds, 3D-QSAR, 2, 4-diamino-7-aminoalkoxyquinazoline
Affiliation:
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China