An investigation on the potential inhibitors of BACE1 using accurate and precise computational approaches was carried out using Autodock4 package. A shortlist of 20 compounds forming the largest docking energy to BACE1 were then refined using steered molecular dynamics (SMD) simulations.

The 20 studied compounds and the ligand 23I had steered molecular dynamics (SMD) simulations performed on them using the GROMACS 5.1.3 package.

Main materials:

• The protein target: β-secretase 1 also called BACE1 (PDB ID: 2p4j)

Steered molecular dynamics (SMD) simulation.

• After docking the compounds by using AutoDock Tools, GROMACS was used to parameterize the protein and water model, and GAUSSIAN was applied to parameterize the ligands. It should be separated in distinct folders with one receptor and one ligand for each. It would include these files: rec.pdb (which is protein, but here means “receptor”), lig.out (the ligand structure was quantum calculated using Gaussian 09 package), top.top, posre.itp.
• After that, use AmberTools generate topology to calculate MD by creating a parameter for ligand in the form of Amber force field then acpype.py will convert it to GROMACS's format.
• Convert MOL_GMX.top into MOL_GMX.itp.
• Combine the ligand parameter with the protein parameter (topology) in top.top file
• Merge the protein and ligand structures together: convert MOL_GMX.gro to MOL_GMX.pdb, concatenate MOL_GMX.pdb into rec.pdb.
• Create PBC triclinic box (box with cyclic boundary conditions) surrounding the complex protein-ligand and solvate (immerse water in the system).
• Restraint C-alpha of receptor. Then include “CA_restr.itp” into top.top.
• Using .mdp files (which is em.mdp, nvt.mdp, npt.mdp and smd.mdp) to add ions, energy minimization, equilibration, and finally performing SMD.