title: Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors.
abstract: Targeting β-secretase (BACE1) with small-molecule inhibitors offers a promising route for treatment of Alzheimer's disease. However, the intricate pH dependence of BACE1 function and inhibitor efficacy has posed major challenges for structure-based drug design. Here we investigate two structurally similar BACE1 inhibitors that have dramatically different inhibitory activity using continuous constant pH molecular dynamics (CpHMD). At high pH, both inhibitors are stably bound to BACE1; however, within the enzyme active pH range, only the iminopyrimidinone-based inhibitor remains bound, while the aminothiazine-based inhibitor becomes partially dissociated following the loss of hydrogen bonding with the active site and change of the 10s loop conformation. The drastically lower activity of the second inhibitor is due to the protonation of a catalytic aspartate and the lack of a propyne tail. This work demonstrates that CpHMD can be used for screening pH-dependent binding profiles of small-molecule inhibitors, providing a new tool for structure-based drug design and optimization.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , Baltimore, Maryland 21201, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Ellis
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , Baltimore, Maryland 21201, United States.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Tsai
authors.affiliation: Neuroscience Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , Baltimore, Maryland 21201, United States.
authors.forename: Jana
authors.initials: J
authors.lastname: Shen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018938:Caco-2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D011480:Protease Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011744:Pyrimidinones / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013876:Thiophenes / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011744:Pyrimidinones; C000603951:SCH1682496; D013876:Thiophenes; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509281:Bace1 protein, rat