Retrospective molecular docking study of WY-25105 ligand to β-secretase and bias of the three-dimensional structure flexibility.

β-Secretase (BACE) is a very promising target in the search for a treatment for Alzheimer's disease using a protein-ligand inhibition approach. Given the many published X-ray structures of BACE protein, structure-based drug design has been used extensively to support new inhibitor discovery programs. Due to the high flexibility and large catalytic site of this protein, sampling of the huge conformational space of the binding site is the big challenge to overcome and is the main limitation of the most widely used docking programs. Incorrect treatment of these pitfalls can introduce bias into ligand docking and could affect the results. This is especially the case with the WY-25105 compound reported by the Wyeth Corporation as a BACE ligand that did not fit into any of the known crystal structures. In the present retrospective study, a set of available X-ray enzyme structures was selected and molecular dynamics simulations were conducted to generate more diverse representative BACE protein conformations. These conformations were then used for a docking study of the WY-25105 compound. The results confirmed the need to use an ensemble of structures in protein-ligand docking for identification of new binding modes in structure-based drug design of BACE inhibitors.