Molecular Dynamics and Docking of Biphenyl: A Potential Attachment Inhibitor for HIV-1 gp120 Glycoprotein

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.