TY - JOUR
T1 - Computational study on the binding and unbinding mechanism of HCV NS5B with the inhibitor GS-461203 and substrate using conventional and steered molecular dynamics simulations
AU - Pan, Dabo
AU - Niu, Yuzhen
AU - Ning, Lulu
AU - Zhang, Yang
AU - Liu, Huanxiang
AU - Yao, Xiaojun
N1 - Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2016
Y1 - 2016
N2 - The active metabolite GS-461203 of hepatitis C virus (HCV) non-structural protein 5B (NS5B) inhibitor sofosbuvir can stall RNA synthesis or replication by competitively inhibiting the natural substrate nucleoside triphosphate like UTP. Unfortunately, S282T mutant can lead to the resistance to sofosbuvir. Here, the detailed binding mechanism and unbinding process of GS-461203 and UTP to HCV NS5B were unraveled by using conventional molecular dynamics (MD) simulation and steered molecular dynamics (SMD) simulation. Our simulation results demonstrate that both polar and nonpolar interactions are favorable for GS-461203 and UTP binding. Meanwhile, we also identified the key residues responsible for GS-461203 and UTP binding in NS5B-RNA together with the three unbinding process steps including translation, reversal of base and ribose and complete divorce. The 2′-fluoro-2′-C-methyl ribose of GS-461203 can form stronger polar and nonpolar interactions with residues S282 and I160 than UTP. The results can also explain the reason why GS-461203 can effectively be incorporated into RNA synthesis or replication. In the S282T mutant system, the binding affinity attenuation of UTP relative to wild type HCV NS5B is less than that of GS-461203. The obtained binding and unbinding mechanism of HCV NS5B with the inhibitor GS-461203 and substrate in our work will provide useful guidance for the development of new and effective HCV NS5B inhibitors with low resistance.
AB - The active metabolite GS-461203 of hepatitis C virus (HCV) non-structural protein 5B (NS5B) inhibitor sofosbuvir can stall RNA synthesis or replication by competitively inhibiting the natural substrate nucleoside triphosphate like UTP. Unfortunately, S282T mutant can lead to the resistance to sofosbuvir. Here, the detailed binding mechanism and unbinding process of GS-461203 and UTP to HCV NS5B were unraveled by using conventional molecular dynamics (MD) simulation and steered molecular dynamics (SMD) simulation. Our simulation results demonstrate that both polar and nonpolar interactions are favorable for GS-461203 and UTP binding. Meanwhile, we also identified the key residues responsible for GS-461203 and UTP binding in NS5B-RNA together with the three unbinding process steps including translation, reversal of base and ribose and complete divorce. The 2′-fluoro-2′-C-methyl ribose of GS-461203 can form stronger polar and nonpolar interactions with residues S282 and I160 than UTP. The results can also explain the reason why GS-461203 can effectively be incorporated into RNA synthesis or replication. In the S282T mutant system, the binding affinity attenuation of UTP relative to wild type HCV NS5B is less than that of GS-461203. The obtained binding and unbinding mechanism of HCV NS5B with the inhibitor GS-461203 and substrate in our work will provide useful guidance for the development of new and effective HCV NS5B inhibitors with low resistance.
KW - Binding free energy calculations
KW - GS-461203
KW - Hepatitis C Virus NS5B RNA-dependent RNA polymerase
KW - Molecular dynamics simulation
UR - http://www.scopus.com/inward/record.url?scp=84979610082&partnerID=8YFLogxK
U2 - 10.1016/j.chemolab.2016.05.015
DO - 10.1016/j.chemolab.2016.05.015
M3 - Article
AN - SCOPUS:84979610082
SN - 0169-7439
VL - 156
SP - 72
EP - 80
JO - Chemometrics and Intelligent Laboratory Systems
JF - Chemometrics and Intelligent Laboratory Systems
ER -