Purpose:
To
develop a new drug that inhibits viral attachment and
entry for the treatment of HIV/AIDS patients.
Methods:
Two
Protein Databank (PDB) crystal structures of HIV-1
gp120-CD4 complexes, namely, 1RZK and 1G9N, were mutated
at amino acid position 43 to a biphenylalanine
(biPhe-43) residue. FireDock web server was used for the
docking experiments and 5ns molecular dynamics (MD)
using Gromacs 4.0 was performed on the protein complexes
to verify the docking results based on the Gibbs free
binding energies.
Results:
Molecular
docking by FireDock web server showed that
biPhe-43
and Trp-43-mutated CD4
inhibited the binding of gp120 more efficiently, -113.8
and -101.7 kJ/mol (SD = 0, n = 3), respectively, than
the alternate aromatic wild type amino acid Phe-43 and
the mutant His-43 and Tyr-43. FireDock revealed that
electrostatic and Van der Waals interactions were mainly
involved in the
CD4-gp120 binding and helped to stabilize the protein
interactions. In a 5ns MD simulation, biPhe-43 and
Trp-43 mutated CD4 demonstrated best Gibbs free binding
energies (-16271 ± 29 and -16266 ± 18 kJ/mol,
respectively) to gp120 in the identification and
confirmation of biPhe-43 and Trp-43 mutated CD4 as
excellent inhibitors to gp120.
Conclusion: The
docked energies and probability outcomes by FireDock
anticipated that a ligand
for an efficient inhibition of HIV gp120 should involve
an extended but conformational flexible aromatic group,
i.e. a biphenyl.
Keywords:
HIV/AIDS,
Attachment inhibitor, gp120-CD4, Molecular docking,
Molecular dynamics, Biphenyl.
