Investigation of pharmacodynamics effect of ten beta-lactam antibiotics on hemagglutinin in the influenza virus type a (h1n1) with drug repositioning approach by in silico method
,1,* Behrokh farahmand
,2 Shima gholami
1. Department of Influenza and other respiratory viruses, Pasteur Institute of Iran, Tehran, Iran.
2. Department of Influenza and other respiratory viruses, Pasteur Institute of Iran, Tehran, Iran.
3. Department of Influenza and other respiratory viruses, Pasteur Institute of Iran, Tehran, Iran.
The h1n1influenza virus is one of the most common pathogen for respiratory infections in the worldwide. this virus is dependent on hemagglutinin for penetrance into the host cell. the part of hemagglutinin called fusion peptide that its function is help to integration of envelope with cell membrane. the purpose of this research with drug repositioning approach is calculation of energy binding between 10 beta-lactam antibiotics and fusion peptide for inhibition of entrance to host cell.
First, the structure of hemagglutinin was retrieved from the rcsb (pdb id: 3lzg) and the fusion peptide region was repaired by the swiss-model server. energy minimization of protein was performed by swiss pdb viewer software with gromos96 force field. pdb files of 10 beta-lactam antibiotics was downloaded from drugbank including cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, temocillin, carbenicillin, azocillin, mecillinam. settings of docking between receptor and ligands were defined by autodocktools software. gridding and docking operations was ruined by cygwin software. also to compare these antibiotics with 2-tert-butylbenzene-1, 4-diol as inhibitor of hemagglutinin in drugbank, docking operation was performed on this inhibitor. according to dlg file, the results were analyzed. in finally, visual representation was prepared and analyzed conformation of best antibiotic in binding site.
According to acquired 10 rmsd tables from 10 ligands, flucloxacillin with binding energy of -5.68 kcal/mol has most appropriate affinity considering probability. in the ranking of 10 antibiotics, methicillin was the last with -4.19 kcal/mol binding energy considering probability. also binding energy of 2-tert-butylbenzene-1, 4-diol was -3.84 kcal/mol. analysis of hydrogen bonds demonstrates that one bond forms between flucloxacillin and glutamine 342 with 2.005 angstrom distance before fusion peptide.
Recently, drug repositioning has attracted for many researchers.with this approach, researchers can find other uses for drugs by reverse docking technique without concerning about pharmacokinetics and toxicity parameters.docking studies demonstrates pharmacodynamics effect of flucloxacillin and dicloxacillin is better than 2-tert-butylbenzene-1, 4-diol as inhibitor of hemagglutinin in drugbank. conformational analysis indicates that fusion peptide was coveredproperly. according to the present study, we suggest to perform more simulations and experimental studies on flucloxacillin.
H1n1influenza, docking, flucloxacillin, drug repositioning