Acylguanidine Beta Secretase 1 Inhibitors: A Combined Experimental and Free Energy Perturbation Study

A series
of acylguanidine beta secretase 1 (BACE1) inhibitors with
modified scaffold and P3 pocket substituent was synthesized and studied
with free energy perturbation (FEP) calculations. The resulting molecules
showed potencies in enzymatic BACE1 inhibition assays up to 1 nM.
The correlation between the predicted activity from the FEP calculations
and the experimental activity was good for the P3 pocket substituents.
The average mean unsigned error (MUE) between prediction and experiment
was 0.68 ± 0.17 kcal/mol for the default 5 ns lambda window simulation
time improving to 0.35 ± 0.13 kcal/mol for 40 ns. FEP calculations
for the P2′ pocket substituents on the same acylguanidine scaffold
also showed good agreement with experiment and the results remained
stable with repeated simulations and increased simulation time. It
proved more difficult to use FEP calculations to study the scaffold
modification from increasing 5 to 6 and 7 membered-rings. Although
prediction and experiment were in agreement for short 2 ns simulations,
as the simulation time increased the results diverged. This was improved
by the use of a newly developed “Core Hopping FEP+”
approach, which also showed improved stability in repeat calculations.
The origins of these differences along with the value of repeat and
longer simulation times are discussed. This work provides a further
example of the use of FEP as a computational tool for molecular design.