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
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.
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