Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study.
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.
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
Weiwei
W
Xue
Ji
J
Qi
Ying
Y
Yang
Xiaojie
X
Jin
Huanxiang
H
Liu
Xiaojun
X
Yao
D004279:DNA, Viral / Q000737:chemistry*; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology*; D000068898:Raltegravir Potassium
D004279:DNA, Viral; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase