期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 24, 期 16, 页码 3849-3855出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.06.031
关键词
Chagas disease; Trypanosoma cruzi; Naphthoquinone derivatives; Tubulin polymerization inhibition; Homology modeling; Binding site prediction; Structure based drug design (SBDD)
资金
- HUMAA (Howard University Medicine Alumni Association)
- NIMHD, NIH [G12 MD007597]
- NSF under the Howard University ADVANCE Institutional Transformation (HU ADVANCE-IT) Grant [1208880]
- NSF-MRI program [CHE-1126533]
- NSF under WBHR-LSAMP Program [0401723]
- Direct For Education and Human Resources
- Division Of Human Resource Development [1208880, 0401723] Funding Source: National Science Foundation
Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson's r value of 0.88 (P value < 0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r = 0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease. (C) 2016 The Authors. Published by Elsevier Ltd.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据