Application of Free Energy Perturbation for the Design of BACE1 Inhibitors

Novel
spiroaminodihydropyrroles probing for optimized interactions
at the P3 pocket of β-secretase 1 (BACE1) were designed with
the use of free energy perturbation (FEP) calculations. The resulting
molecules showed pIC50 potencies in enzymatic BACE1 inhibition
assays ranging from approximately 5 to 7. Good correlation was observed
between the predicted activity from the FEP calculations and experimental
activity. Simulations run with a default 5 ns approach delivered a
mean unsigned error (MUE) between prediction and experiment of 0.58
and 0.91 kcal/mol for retrospective and prospective applications,
respectively. With longer simulations of 10 and 20 ns, the MUE was
in both cases 0.57 kcal/mol for the retrospective application, and
0.69 and 0.59 kcal/mol for the prospective application. Other considerations
that impact the quality of the calculations are discussed. This work
provides an example of the value of FEP as a computational tool for
drug discovery.