摘要
Sigma-1受体(Sigma-1 receptor,σ1R)主要参与调节细胞应激反应和细胞稳态,并与许多神经退行性疾病及肿瘤的发生发展密切相关。烷氧基异恶唑类化合物是一种新型的σ1R受体抑制剂,对σ1R具有较好的抑制活性,最优化合物与σ1R之间的结合常数小于1 nm。为了探究立体效应对这一类抑制剂与σ1R相互作用的影响,应用分子对接、分子动力学模拟和结合自由能计算;对比研究了3个σ1R抑制剂(20、37和54)与σ1R之间的相互作用方式和结合强度。研究表明,具有较大头端疏水区和质子供体N原子区的化合物54与σ1R之间的结合强度最大,这与实验测得的结合常数一致。此外,还计算了σ1R抑制剂与σ1R之间相互作用的能量分项。结果表明,范德华相互作用对该类抑制剂与σ1R之间的相互作用起主导作用;而静电相互作用的影响较小。基于氨基酸残基的结合自由能分解及对抑制剂与σ1R结合构象的分析表明,提高头端疏水区和质子供体N原子区的立体体积,有利于提高该类抑制剂与σ1R之间的结合活性。
Sigma-1 receptor(σ1 R) involves in regulating cellular stress response and cell homeostasis,which is closely related to the occurrence and development of many neurodegenerative diseases and tumors. Alkoxyisoxazoles,a novel kind of σ1 R antagonist,have good inhibitory activity to σ1 R. The best binding affinity to σ1 R is less than 1 nm. To explore the influence of steric effect on the inhibitor …σ1 R interaction,molecular docking,molecular dynamics simulation and binding free energy calculation were carried to study the interaction modes and strength of three alkoxyisoxazoles( 20,37,54) with σ1 R. Results show 54 with the big-sized head-hydrophobic and proton donor( N atom) regions has the highest binding strength,consisting with the experiment. Compared with the electrostatic interaction,van der Waals interaction plays a more important role in the binding of alkoxyisoxazole inhibitors to σ1 R. Residue-based energetic decomposition and analyses on binding conformations reveal that increasing the size of head-hydrophobic region and proton donor region is favor to the binding activity of alkoxyisoxazole inhibitors.
作者
罗宏华
谢晓曦
张卓琳
蒋南
LUO Hong-hua;XIE Xiao-xi;ZHANG Zhuo-lin;JIANG Nan(School of Pharmacy,Nanjing Medical University,Nanjing 211100,China)
出处
《科学技术与工程》
北大核心
2019年第10期37-44,共8页
Science Technology and Engineering
基金
国家自然科学基金(21303086)
江苏省大学生创新创业训练计划(201710312027Z)资助
