title: Combining NMR and X-ray crystallography in fragment-based drug discovery: discovery of highly potent and selective BACE-1 inhibitors.
abstract: Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade. We review here how we have used highly structure-driven fragment-based approaches to complement more traditional lead discovery to tackle high priority targets and those struggling for leads. Combining biomolecular nuclear magnetic resonance (NMR), X-ray crystallography, and molecular modeling with structure-assisted chemistry and innovative biology as an integrated approach for FBDD can solve very difficult problems, as illustrated in this chapter. Here, a successful FBDD campaign is described that has allowed the development of a clinical candidate for BACE-1, a challenging CNS drug target. Crucial to this achievement were the initial identification of a ligand-efficient isothiourea fragment through target-based NMR screening and the determination of its X-ray crystal structure in complex with BACE-1, which revealed an extensive H-bond network with the two active site aspartate residues. This detailed 3D structural information then enabled the design and validation of novel, chemically stable and accessible heterocyclic acylguanidines as aspartic acid protease inhibitor cores. Structure-assisted fragment hit-to-lead optimization yielded iminoheterocyclic BACE-1 inhibitors that possess desirable molecular properties as potential therapeutic agents to test the amyloid hypothesis of Alzheimer's disease in a clinical setting.
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA. daniel.wyss@merck.com
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wyss
authors.forename: Yu-Sen
authors.initials: YS
authors.lastname: Wang
authors.forename: Hugh L
authors.initials: HL
authors.lastname: Eaton
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Voigt
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D054852:Small Molecule Libraries / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D053829:Amyloid Precursor Protein Secretases