title: Acylguanidine Beta Secretase 1 Inhibitors: A Combined Experimental and Free Energy Perturbation Study.
abstract: 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.
authors.affiliation: Computational Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Henrik
authors.initials: H
authors.lastname: Keränen
authors.affiliation: Laboratori de Medicina Computacional Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona , 08193, Bellaterra, Spain.|Computational Chemistry, Janssen Research and Development, Janssen-Cilag , c/ Jarama 75A, 45007, Toledo, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Pérez-Benito
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Janssen-Cilag , c/ Jarama 75A, 45007, Toledo, Spain.
authors.forename: Myriam
authors.initials: M
authors.lastname: Ciordia
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Janssen-Cilag , c/ Jarama 75A, 45007, Toledo, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Delgado
authors.affiliation: Schrödinger GmbH , Dynamostrasse 13, 68165 Mannheim, Baden-Württemberg, Germany.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Steinbrecher
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oehlrich
authors.affiliation: Computational Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Herman W T
authors.initials: HW
authors.lastname: van Vlijmen
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Janssen-Cilag , c/ Jarama 75A, 45007, Toledo, Spain.
authors.forename: Andrés A
authors.identifier: http://orcid.org/0000-0002-4225-758X
authors.initials: AA
authors.lastname: Trabanco
authors.affiliation: Computational Chemistry, Janssen Research and Development, Janssen-Cilag , c/ Jarama 75A, 45007, Toledo, Spain.
authors.forename: Gary
authors.identifier: http://orcid.org/0000-0002-4801-1644
authors.initials: G
authors.lastname: Tresadern
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D019791:Guanidine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D019791:Guanidine