Application of Free Energy Perturbation for the Design of BACE1 Inhibitors

Myriam Ciordia, Laura Pérez-Benito, Francisca Delgado, Andrés A. Trabanco, Gary Tresadern

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78 Citations (Scopus)


© 2016 American Chemical Society. 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.
Original languageEnglish
Pages (from-to)1856-1871
JournalJournal of Chemical Information and Modeling
Issue number9
Publication statusPublished - 26 Sep 2016


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