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基于结构的药效团与3D-QSAR联合研究苯丙氨酸系列化合物作为色氨酸羟化酶1抑制剂的作用

Combined structure-based pharmacophore and 3D-QSAR studies on phenylalanine series compounds as TPH1 inhibitors.

作者信息

Ouyang Liang, He Gu, Huang Wei, Song Xiangrong, Wu Fengbo, Xiang Mingli

机构信息

State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

State Key Laboratory Breeding Base of Systematic research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610041, China.

出版信息

Int J Mol Sci. 2012;13(5):5348-5363. doi: 10.3390/ijms13055348. Epub 2012 May 2.

DOI:10.3390/ijms13055348
PMID:22754301
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3382768/
Abstract

Tryptophan hydroxylase-1 (TPH1) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. In this study, a combination of ligand-based and structure-based methods is used to clarify the essential quantitative structure-activity relationship (QSAR) of known TPH1 inhibitors. A multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of TPH1 kinase based on three crystal structures of TPH1-inhibitor complex. This model has been successfully used to identify the bioactive conformation and align 32 structurally diverse substituted phenylalanine derivatives. The QSAR analyses have been performed on these TPH1 inhibitors based on the MCBP guided alignment. These results may provide important information for further design and virtual screening of novel TPH1 inhibitors.

摘要

色氨酸羟化酶-1（TPH1）是血清素合成中的关键酶。作为一种神经递质，血清素在周围和中枢都发挥着重要的生理作用。在本研究中，基于配体和基于结构的方法相结合，以阐明已知TPH1抑制剂的基本定量构效关系（QSAR）。有人提出了一种基于多复合物的药效团（MCBP）导向方法，以基于TPH1-抑制剂复合物的三种晶体结构生成TPH1激酶的综合药效团。该模型已成功用于识别生物活性构象并对齐32种结构多样的取代苯丙氨酸衍生物。基于MCBP导向对齐对这些TPH1抑制剂进行了QSAR分析。这些结果可能为新型TPH1抑制剂的进一步设计和虚拟筛选提供重要信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e864/3382768/261540bb6aef/ijms-13-05348f7.jpg
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