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KMID : 0617320080190010058
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Journal of Pharmacetical Sceiences Ewha Womans University
2008 Volume.19 No. 1 p.58 ~ p.65
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3D-QSAR studies of heterocyclic quinones with inhibitory activity on vascular smooth muscle cell proliferation using pharmacophore-based alignment
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Ryu Chung-Kyu
Lee Yoon-Ji
Park Seul-Gi
You Hea-Jung
Lee Ra-Young
Lee Seung-Yon
Choi Sun
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Abstract
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The abnormal proliferation and migration of vascular smooth muscle cells (SMCs) play an important role in the pathology of coronary artery atherosclerosis and restenosis following angioplasty. It was reported that some heterocyclic quinone derivatives such as 6-arylamino-quinoxaline-5,8-diones and 6-arylamino-1H-benzo[d]imidazole-4,7-diones have inhibitory activity on rat aortic smooth muscle cell (RAoSMC) proliferation. To understand the structural basis for antiproliferative activity to design more potent agents, we generated pharmacophore models of representative molecules with high activity using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD) and aligned a series of compounds to the selected pharmacophore model, then performed three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA).
Good cross-validated correlations were obtained with CoMFA (resulting in q² of 0.734 and r² of 0.947) and CoMSIA (resulting in q² of 0.736 and r² of 0.913). The IC_(50) values of the heterocyclic quinone derivatives on RAoSMC exhibited a strong correlation with steric and hydrophobic fields of the 3D structure of the molecules, resulting in the reliable prediction of inhibitory activity of the series of compounds.
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KEYWORD
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Antiproliferative, Vascular smooth muscle cell, QSAR, CoMFA, CoMSIA, Quinoxaline-5, 8-dione, 1H-benzo[d]imidazole-4, 7-dione
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