Molecular Dynamics Study On Drug Resistance Mechanism Of HCV NS3/4A Protease Inhibitor: BI201335

Hepatitis C Virus (HCV) infection is a serious threat to global health. It is about170million people worldwide are infected with HCV. The standard treatment of HCVinfection is a combination of pegylated interferon α and ribavirin (Peg-IFN/RBV)produces sustained virological response only about50%of HCV patient. The targetenzymes include HCV NS3/4A serine protease, HCV NS5A protease and HCV NS5Bpolymerase protease, while the HCV NS3/4A serine protease is one of the mostadvanced HCV drug targets. Two ketoamide inhibitors boceprevir and telaprevir havebeen approved by FDA in2011. However, the high mutation rate makes manyprotease inhibitors ineffective and allows viral replication to occur.BI201335is a promising drug candidate that targets the viral NS3/NS4A serineprotease developed by Boehringer Ingelheim Incorporation is now in phase III clinicaltrials，and the researchers reported the resistance caused to BI201335includingA156V/T, R155K/Q and D168A/G/V. However, no research has been reported inanalysis the drug resistance mechanism to BI201335. Our work is to investigate thestructural basis of molecular mechanism of HCV resistance to BI201335, moleculardynamics and molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA)calculations were carried out on those complexes. The drug resistance to theBI201335is explained by the fact that seven single mutations weaken biologicalactivity by way of lessening the sum of electrostatic interactions in the gas phase andpolar solvation. The computational results demonstrate that the mutations affect theBI201335binding through direct and indirect mechanism. Seven single mutationslead to significant conformation changes, such as the shifts of the side chain of His57and Lys136, and the movement of the P2group of BI201335toward the solvent.Further, the contributions of Lys136significantly decrease, which is the most majorbinding attraction. The shifts of the side chain of His57induce the lack of hydrogenbond between His57with Asp81expert for D168G mutation. These detailed insightsinto the mechanism of BI201335resistance will be very useful to structure-baseddesign of novel inhibitors that will be less susceptible to resistance.