Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study

doi:10.1039/c2mb25114k

	Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study
	Xue, Weiwei 1; Qi, Ji2 ; Yang, Ying 1; Jin, Xiaojie 1; Liu, Huanxiang 3; Yao, Xiaojun 1,4
刊名	MOLECULAR BIOSYSTEMS
	2012
卷号	8 页码:2135-2144
ISSN号	1742-206X
DOI	10.1039/c2mb25114k
文献子类	Article
英文摘要	Raltegravir is the first FDA-approved drug targeting the strand transfer step of HIV-1 integration. However, the rapid emergence of viral strains that are highly resistant to raltegravir has become a critical problem. Unfortunately, the detailed molecular mechanism of how HIV-1 integrase (IN) mutations actually confer drug resistance is not well understood. In the present study, starting from our previously constructed complex of HIV-1 IN and viral DNA, we employed molecular dynamics (MD) simulation and molecular mechanics generalized Born surface area (MM-GBSA) calculation, to uncover the molecular mechanism behind the resistant mechanism of HIV-1 IN to raltegravir. The values of the calculated binding free energy follow consistently the experimentally observed ranking of resistance levels. A detailed analysis of the results of MD simulation suggests that the Tyr143 located in the 140s loop (e. g., residues from Gly140 to Gly149) is a key anchoring residue that leads to stable raltegravir binding. The decrease in the interaction at this residue is one of the key reasons responsible for the resistance of HIV-1 IN to raltegravir. Additionally, the calculation results also proved that the 3' adenosine flip in different conformations in the wild-type and mutant HIV-1 IN-viral DNA complexes play an important role in raltegravir binding. Our results could provide a structural and energetic understanding of the raltegravir-resistant mechanism at the atomic level and provide some new clues on how to design new drugs that may circumvent the known resistance mutations.
资助项目	Fundamental Research Funds for the Central Universities[lzujbky-2011-19] ; Fundamental Research Funds for the Central Universities[lzujbky-2012-k10]
WOS关键词	IMMUNODEFICIENCY-VIRUS TYPE-1 ; FREE-ENERGY CALCULATIONS ; INTEGRASE INHIBITORS ; STRAND TRANSFER ; IN-VITRO ; DYNAMICS SIMULATIONS ; RESP METHODOLOGY ; SOLVENT MODELS ; FORCE-FIELD ; BINDING
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000305965100012
内容类型	期刊论文
源URL	[http://119.78.100.186/handle/113462/47749]
专题	中国科学院近代物理研究所
通讯作者	Yao, Xiaojun
作者单位	1.Lanzhou Univ, Dept Chem, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China 2.Chinese Acad Sci, Inst Modern Phys, Lanzhou 730000, Peoples R China 3.Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China 4.Lanzhou Univ, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China
推荐引用方式 GB/T 7714	Xue, Weiwei,Qi, Ji,Yang, Ying,et al. Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study[J]. MOLECULAR BIOSYSTEMS,2012,8:2135-2144.
APA	Xue, Weiwei,Qi, Ji,Yang, Ying,Jin, Xiaojie,Liu, Huanxiang,&Yao, Xiaojun.(2012).Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study.MOLECULAR BIOSYSTEMS,8,2135-2144.
MLA	Xue, Weiwei,et al."Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study".MOLECULAR BIOSYSTEMS 8(2012):2135-2144.