Binding mode prediction of aplysiatoxin, a potent agonist of protein kinase C, through molecular simulation and structure-activity study on simplified analogs of the receptor-recognition domain
Binding mode prediction of aplysiatoxin, a potent agonist of protein kinase C, through molecular simulation and structure-activity study on simplified analogs of the receptor-recognition domain
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DOI：
10.1016/j.bmc.2016.07.011
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发表时间：
2016-09-15
影响因子：
3.5
通讯作者：
Irie, Kazuhiro
中科院分区：
文献类型：
--
作者：
Ashida, Yoshiki;Yanagita, Ryo C.;Irie, Kazuhiro
Aplysiatoxin(ATX)是从海兔和蓝藻中分离出来的一种自然产生的肿瘤促进剂。ATX与蛋白激酶C(PKC)同工酶结合并激活，对人类癌细胞具有抗增殖活性。近年来，ATX作为一种新型抗癌药物的先导化合物引起了人们的关注。为了预测ATX与蛋白激酶C Delta(PKC Delta)C1B结构域的结合方式，我们对ATX进行了分子对接模拟、磷脂膜环境下的原子分子动力学模拟和一个简单的非环类似物ATX的构效关系研究。这些研究提供了ATX上27位的羰基、30位的羟基和20位的酚羟基参与了与PKC Delta C1B结构域的分子间氢键的结合模型，这将有助于ATX衍生物作为抗癌先导化合物的合理设计。(C)2016爱思唯尔有限公司。保留所有权利。
Aplysiatoxin (ATX) is a naturally occurring tumor promoter isolated from a sea hare and cyanobacteria. ATX binds to, and activates, protein kinase C (PKC) isozymes and shows anti-proliferative activity against human cancer cell lines. Recently, ATX has attracted attention as a lead compound for the development of novel anticancer drugs. In order to predict the binding mode between ATX and protein kinase C delta (PKC delta) C1B domain, we carried out molecular docking simulation, atomistic molecular dynamics simulation in phospholipid membrane environment, and structure-activity study on a simple acyclic analog of ATX. These studies provided the binding model where the carbonyl group at position 27, the hydroxyl group at position 30, and the phenolic hydroxyl group at position 20 of ATX were involved in intermolecular hydrogen bonding with the PKC delta C1B domain, which would be useful for the rational design of ATX derivatives as anticancer lead compounds. (C) 2016 Elsevier Ltd. All rights reserved.