Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies
文献类型：期刊论文
| 作者 | Li, Jing2 ; Du, Yun2; Liu, Xian2; Shen, Qian-cheng2; Huang, Ai-long1; Zheng, Ming-yue2; Luo, Xiao-min2; Jiang, Hua-liang2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2013-02 |
| 卷号 | 34期号:2页码:319-328 |
| 关键词 | hepatitis HBV polymerase genotype adefovir molecular dynamics simulation free energy calculation |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2012.146 |
| 文献子类 | Article |
| 英文摘要 | Aim: To investigate the molecular mechanisms underlying the influence of DNA polymerase from different genotypes of hepatitis B virus (HBV) on the binding affinity of adefovir (ADV). Methods: Computational approaches, including homology modeling, docking, MD simulation and MM/PBSA free energy analyses were used. Results: Sequence analyses revealed that residue 238 near the binding pocket was not only a polymorphic site but also a genotype-specific site (His238 in genotype B; Asn238 in genotype C). The calculated binding free-energy supported the hypothesis that the polymerase from HBV genotype C was more sensitive to ADV than that from genotype B. By using MD simulation trajectory analysis, binding free energy decomposition and alanine scanning, some energy variation in the residues around the binding pocket was observed. Both the alanine mutations at residues 236 and 238 led to an increase of the energy difference between genotypes C and B (Delta Delta G(C-B)), suggesting that these residues contributed to the genotype-associated antiviral variability with regard to the interaction with ADV. Conclusion: The results support the hypothesis that the HBV genotype C polymerase is more sensitive to ADV than that from genotype B. Moreover, residue N236 and the polymorphic site 238 play important roles in contributing to the higher sensitivity of genotype C over B in the interaction with ADV. |
| WOS关键词 | HEPATITIS-B-VIRUS ; ANTIVIRAL RESISTANCE MUTATIONS ; AMBER FORCE-FIELD ; REVERSE-TRANSCRIPTASE ; HEPATOCELLULAR-CARCINOMA ; DIPIVOXIL THERAPY ; CHINESE PATIENTS ; FREE-ENERGIES ; LAMIVUDINE ; PHASE |
| 资助项目 | State Key Laboratory of Drug research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[00000000] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[81001399] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4743824 |
| WOS记录号 | WOS:000315131300021 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277744]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 国家新药筛选中心 |
| 通讯作者 | Huang, Ai-long |
| 作者单位 | 1.Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Minist Educ, Chongqing 400016, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Li, Jing,Du, Yun,Liu, Xian,et al. Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies[J]. ACTA PHARMACOLOGICA SINICA,2013,34(2):319-328. |
| APA | Li, Jing.,Du, Yun.,Liu, Xian.,Shen, Qian-cheng.,Huang, Ai-long.,...&Jiang, Hua-liang.(2013).Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies.ACTA PHARMACOLOGICA SINICA,34(2),319-328. |
| MLA | Li, Jing,et al."Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies".ACTA PHARMACOLOGICA SINICA 34.2(2013):319-328. |
入库方式： OAI收割
来源：上海药物研究所
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