De novo design of novel selective COX-2 inhibitors: From virtual screening to pharmacophore analysis
De novo design of novel selective COX-2 inhibitors: From virtual screening to pharmacophore analysis
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DOI：
10.1016/j.jtice.2008.06.001
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发表时间：
2009-01-01
影响因子：
5.7
通讯作者：
Chen, Calvin Yu-Chian
中科院分区：
文献类型：
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作者：
Chen, Calvin Yu-Chian
本研究选择多种抗癌活性化合物对人环氧合酶-2（考克斯-2）进行选择性抑制的模拟实验。根据我们的模型，Leu 530和Ile 522将导致考克斯-1结合位点呈隧道样。B组化合物适用于考克斯-1。一般来说，较大的化合物，A组。D、YC-1衍生物对考克斯-2的适应性更强。然而，黄酮类化合物对这两种酶的选择性影响不显着。在考克斯-2的Tyr 371和Trp 373附近引入蒽醌基更合适，而从头设计引入的羟基与Arg 106/Tyr 341门相互作用，使配体更稳定。在基团D方面，一个候选物上的稠合的羟基和异丙基基团试图与门相互作用，这导致整个结构更稳定。此外，在某些候选分子上融合的疏水基团结合在Ser 516和Tyr 371之间，可以稳定活性位点的整体构象。结果表明，杨梅素上的乙炔基可能是有效的药效团，而活性中心的门与Ser 516和Tyr 371之间的疏水区之间的氢键相互作用对考克斯-2活性中心的配体结合起重要作用。(c)2008台湾化学工程师学会。Elsevier B. V.出版，保留所有权利。
Various potent anti-cancer compounds were recruited for the simulation trails of selective inhibition to human cyclooxygenase-2 (COX-2). From our modeling, Leu530 and Ile522 would cause the COX-1 binding site tunnel-like. Compounds of group B would be suitable in COX-1. Contrarily, the larger compounds, group A. D, and YC-1 derivatives were more adaptable in COX-2. However, flavonoids had insignificant selective effects against both enzymes. The anthraquinonyl group could be more suitable near the Tyr371 and Trp373 of COX-2, and the added hydroxyl group from de novo design interacted with Arg106/Tyr341 gate would lead the ligand to stabilize. In aspect of group D, the fused hydroxyl and aldehydyl group on one candidate attempted to interact with the gate, which induced the whole construction more stable. Besides, the hydrophobic groups, which fused on some candidates and bound between Ser516 and Tyr371, could stabilize the whole conformations in active site. We found the ethynyl groups added on myricetin Could be effective pharmacophores, and the H-bond interactions between the gate of active site and the hydrophobic region among Ser516 and Tyr371 were important for the bound ligands in COX-2 active site. (c) 2008 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.