Understanding the drug resistance mechanism of hepatitis C virus NS3/4A to ITMN-191 due to R155K, A156V, D168A/E mutations: a computational study.
BACKGROUND
ITMN-191 (RG7227, Danoprevir), as a potential inhibitor of the NS3/4A protease of hepatitis C virus, has been in phase 2 clinical trial. Unfortunately, several ITMN-191 resistance mutants including R155K, A156V, and D168A/E have been identified.


METHODS
Molecular dynamics simulation, binding free energy calculation and per-residue energy decomposition were employed to explore the binding and resistance mechanism of hepatitis C virus NS3/4A protease to ITMN-191.


RESULTS
Based on molecular dynamics simulation and per-residue energy decomposition, the nonpolar energy term was found to be the driving force for ITMN-191 binding. For the studied R155K, A156V, D168A/E mutants, the origin of resistance is mainly from the conformational changes of the S4 and extended S2 binding pocket induced by the studied mutants and further leading to the reduced binding ability to the extended P2 and P4 moieties of ITMN-191.


CONCLUSIONS
Further structural analysis indicates that the destruction of conservative salt bridges between residues 168 and 155 should be responsible for the large conformation changes of the binding pocket in R155K and D168A/E mutants. For A156V mutation, the occurrence of drug resistance is mainly from the changed binding pocket by a replacement of one bulky residue Val.


CONCLUSIONS
The obtained drug resistance mechanism of this study will provide useful guidance for the development of new and effective HCV NS3/4A inhibitors with low resistance.
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Dabo
D
Pan
Weiwei
W
Xue
Wenqi
W
Zhang
Huanxiang
H
Liu
Xiaojun
X
Yao
D000409:Alanine / Q000737:chemistry / Q000235:genetics; D019943:Amino Acid Substitution / Q000502:physiology; D000998:Antiviral Agents / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics; D032882:Comprehension; D019295:Computational Biology; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics* / Q000502:physiology; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics; D016174:Hepacivirus / Q000737:chemistry / Q000201:enzymology / Q000235:genetics*; D054833:Isoindoles; D007769:Lactams / Q000494:pharmacology*; D047029:Lactams, Macrocyclic; D008239:Lysine / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense / Q000502:physiology*; D011392:Proline / Q000031:analogs & derivatives; D013449:Sulfonamides / Q000494:pharmacology*; D014633:Valine / Q000737:chemistry / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000409:Alanine; D000998:Antiviral Agents; D001120:Arginine; D001224:Aspartic Acid; D003521:Cyclopropanes; D018698:Glutamic Acid; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D008239:Lysine; D011392:Proline; D013449:Sulfonamides; D014633:Valine; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C553752:danoprevir