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 PAC-PB1N 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 PAC-PB1N of Influenza A/2009 (H1N1).
Highlights
Since March 2009, a new strain of Influenza A/H1N1 flu has spread rapidly and become a pandemic
The docking process was performed on 1728 cyclopentadienyl peptide inhibitors into Polymerase A (PA)-Polymerase B1 (PB1) protein
Unlike the other two binding sites, The Trp706 and Phe411 binding sites have a great contribution to the bonding interactions of polymerase PA-PB1 (Liu and Yao, 2010)
Summary
Since March 2009, a new strain of Influenza A/H1N1 flu has spread rapidly and become a pandemic. The H1N1 virus infection has been officially reported in many countries (WHO, 2014). This could be a big burden to the health care system in the world due to the high mortality and morbidity associated with H1N1 pandemics (Donaldson et al, 2009). The rapid mutation of influenza virus showed several strains of drug resistance (Regoes and Bonhoeffer, 2006). The hydrophobic pockets of PAC-PB1N crystal structure were located on the molecular surface. Hydrophobic pockets would facilitate an array of hydrogen bonds in the PAC-PB1N (Moen et al, 2014). It is required for the PA that contains residues (Perez and Donis, 2001)
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