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

作者：Keranen Henrik; Perez Benito Laura; Ciordia Myriam; Delgado Francisca; Steinbrecher Thomas B; Oehlrich Daniel; van Vlijmen Herman W T; Trabanco Andres A; Tresadern Gary^*

来源：Journal of Chemical Theory and Computation, 2017, 13(3): 1439-1453.

DOI：10.1021/acsjctc.6b01141

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 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.

• 出版日期2017-3