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.
Medicinal Chemistry
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
Volume: 10 Issue: 4
Author(s): Taotao Feng, Hai Wang, Xiaojin Zhang, Haopeng Sun and Qidong You
Affiliation:
Keywords: CoMSIA, G9a inhibitors, molecular modeling, novel compounds, 3D-QSAR, 2, 4-diamino-7-aminoalkoxyquinazoline.
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.
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Feng Taotao, Wang Hai, Zhang Xiaojin, Sun Haopeng and You Qidong, 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, Medicinal Chemistry 2014; 10 (4) . https://dx.doi.org/10.2174/15734064113096660068
DOI https://dx.doi.org/10.2174/15734064113096660068 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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