摘要
目的通过分子动力学模拟研究化合物Cpd-22选择性靶向β分泌酶-1(BACE-1)而非其同源蛋白β分泌酶-2(BACE-2)的选择性机制。方法采用分子动力学模拟技术,通过均方根偏差计算,评价化合物Cpd-22对BACE-1和BACE-2蛋白波动的影响;通过主成分分析,评价BACE-1和BACE-2蛋白结合Cpd-22的构象分布;通过溶剂可及表面积分析,评价BACE-1和BACE-2蛋白结合Cpd-22的蛋白在溶质中的稳定性;最后,通过结合自由能的计算与关键氨基酸残基,凸显BACE-1和BACE-2蛋白结合Cpd-22选择性差异的关键氨基酸残基。结果均方根偏差结果显示化合物Cpd-22在BACE-1中的波动明显小于在BACE-2中,说明Cpd-22在BACE-1中更为稳定。主成分分析研究显示,Cpd-22在BACE-1的构象相比BACE-2中的分布更为集中,验证了Cpd-22在BACE-1的构象变化小的结论。溶剂可及表面积分析同样显示,在溶质中,Cpd-22在BACE-1中的构象相比在BACE-2中更为稳定。关键氨基酸残基分解显示,氢键相互作用的关键氨基酸残基包括Gln97、Gly98等,是Cpd-22选择性靶向BACE-1的关键。结论本研究从动态结构上分析了选择性靶向BACE-1的构象变化和关键氨基酸残基,为后续靶向BACE-1的选择性抑制剂提供了设计思路。
Molecular dynamics simulation was used in order to investigate the mechanism of the compound Cpd-22 selectively targetingβ-site amyloid precursor protein-cleaving enzyme 1(BACE-1)instead of its homologueβ-site amyloid precursor protein-cleaving enzyme 2(BACE-2).The root-mean-square deviation(RMSD)was applied to evaluate the protein fluctuations of Cpd-22 bound with BACE-1 and BACE-2.The principal component analysis was performed to evaluate the conformational distributions of Cpd-22 bound with BACE-1 and BACE-2.Then,the solvent-accessible surface area analysis was utilized to the assessment of the stability of BACE-1 and BACE-2 proteins bound to Cpd-22 in solutes.Finally,the key amino acid residues of BACE-1 and BACE-2 proteins bound with Cpd-22 were identified by free energy calculations and key amino acid residues decomposition.RMSD analysis results showed that the fluctuation of compound Cpd-22 bound with BACE-1 was quite smaller than those in BACE-2,indicating that Cpd-22 was more stable bound with BACE-1 than BACE-2.Subsequently,principal component analysis further showed that Cpd-22 had a more concentrated conformational distribution in BACE-1 than BACE-2,which verified that Cpd-22 had a small conformational change in BACE-1.Solvent-accessible surface area analysis also showed that the conformation of Cpd-22 in BACE-1 in the solute was more stable than in BACE-2.Decomposition of key amino acid residues revealed that key amino acid residues of offer hydrogen bonding interactions including Gln97,Gly98,etc.are vital for Cpd-22 selectively targeting BACE-1.Overall,the conformational changes and key amino acid residues of BACE-1 identified from this provided a design clue for the development of selective inhibitors targeting BACE-1.
作者
周璇
许丹华
ZHOU Xuan;XU Dan-hua(Department of Pharmacy,Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province,Affiliated Hangzhou First People's Hospital,Zhejiang University School of Medicine,Hangzhou 310006,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2020年第7期399-404,共6页
Chinese Journal of Medicinal Chemistry
