title: Application of Free Energy Perturbation for the Design of BACE1 Inhibitors.
abstract: 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.
authors: Janssen Research and Development , c/Jarama 75A, 45007 Toledo, Spain.|Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo , Urbanización Montepríncipe Ctra., Boadilla del Monte Km 5.3, 28668 Madrid, Spain.
authors: Myriam
authors: M
authors: Ciordia
authors: Janssen Research and Development , c/Jarama 75A, 45007 Toledo, Spain.|Laboratori de Medicina Computacional Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona , 08193 Bellaterra, Spain.
authors: Laura
authors: L
authors: Pérez-Benito
authors: Janssen Research and Development , c/Jarama 75A, 45007 Toledo, Spain.
authors: Francisca
authors: F
authors: Delgado
authors: Janssen Research and Development , c/Jarama 75A, 45007 Toledo, Spain.
authors: Andrés A
authors: AA
authors: Trabanco
authors: Janssen Research and Development , c/Jarama 75A, 45007 Toledo, Spain.
authors: Gary
authors: G
authors: Tresadern
mesh_terms: D000578:Amidines / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D000578:Amidines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases