Designing of Disulfide Cyclic Peptide for Inhibiting Polymerase A and B1 (PA_C-PB1_N) in H1N1 Virus using Molecular Simulation Approach

Abstract

The drug resistance A/H1N1 flu virus is emerging rapidly. Therefore, looking for potential therapy is very important. PB2, PB and PA are subunits of viral RNA-dependent RNA polymerase (RdRp). They play an important role in viral replication. The PA and PB1 binding sites can be considered as potential targets for the development of new influenza drugs. The peptide inhibitors can be designed specifically due to their high-preferred activity. In this study, the cyclic peptide ligands were designed based on the crystal structure of PA_C-PB1_N in the surface of the molecule, resulting 1728 cyclopentadienyl compounds. The MOE 2008.10 software was utilized for molecular docking and dynamics simulation approach, while Lipinski’s Rules of Five were utilized to evaluate the feasibility of drug candidates. Thus, molecular dynamics simulation was applied, in order to facilitate the interaction between the ligand and enzyme. The simulations have successfully produced two cyclopentyl peptides, namely CKKTC and CKTTC, which results in both ligands providing a potent inhibitor of polymerase PA_C-PB1_N of Influenza A/2009 (H1N1).