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Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of β-Secretase.

Jordan JB, Whittington DA, Bartberger MD, Sickmier EA, Chen K, Cheng Y, Judd T
J Med Chem 59 3732-49 (2016)
Related entries: 5i3w, 5i3x, 5i3y, 5ie1

Cited: 23 times
EuropePMC logo PMID: 26978477

Abstract

Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with (19)F NMR-based methods has been shown to provide several advantages over (1)H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of (19)F-based fragment screening by detailing the identification of a second-site fragment through (19)F NMR screening that binds to a specific pocket of the aspartic acid protease, β-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment-linking approach, which ultimately yielded a molecule exhibiting a more than 360-fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling.

Reviews citing this publication (8)

  1. Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment. Coimbra JRM, Marques DFF, Baptista SJ, Pereira CMF, Moreira PI, Dinis TCP, Santos AE, Salvador JAR. Front Chem 6 178 (2018)
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  6. NMR-Fragment Based Virtual Screening: A Brief Overview. Singh M, Tam B, Akabayov B. Molecules 23 E233 (2018)
  7. 19F NMR viewed through two different lenses: ligand-observed and protein-observed 19F NMR applications for fragment-based drug discovery. Buchholz CR, Pomerantz WCK. RSC Chem Biol 2 1312-1330 (2021)
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Articles citing this publication (15)

  1. Protein-Observed Fluorine NMR Is a Complementary Ligand Discovery Method to 1H CPMG Ligand-Observed NMR. Urick AK, Calle LP, Espinosa JF, Hu H, Pomerantz WC. ACS Chem Biol 11 3154-3164 (2016)
  2. Impact of a Central Scaffold on the Binding Affinity of Fragment Pairs Isolated from DNA-Encoded Self-Assembling Chemical Libraries. Bigatti M, Dal Corso A, Vanetti S, Cazzamalli S, Rieder U, Scheuermann J, Neri D, Sladojevich F. ChemMedChem 12 1748-1752 (2017)
  3. 19 F NMR transverse and longitudinal relaxation filter experiments for screening: a theoretical and experimental analysis. Dalvit C, Piotto M. Magn Reson Chem 55 106-114 (2017)
  4. Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond. Ai Y, Hwang L, MacKerell AD, Melnick A, Xue F. J Med Chem 64 4333-4358 (2021)
  5. From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein-Templated Synthesis. Nozal V, García-Rubia A, Cuevas EP, Pérez C, Tosat-Bitrián C, Bartolomé F, Carro E, Ramírez D, Palomo V, Martínez A. Angew Chem Int Ed Engl 60 19344-19354 (2021)
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  8. Selective Binding of Small Molecules to Vibrio cholerae DsbA Offers a Starting Point for the Design of Novel Antibacterials. Wang G, Mohanty B, Williams ML, Doak BC, Dhouib R, Totsika M, McMahon RM, Sharma G, Zheng D, Bentley MR, Ka-Yan Chin Y, Horne J, Chalmers DK, Heras B, Scanlon MJ. ChemMedChem 17 e202100673 (2022)
  9. 19 F NMR isotropic chemical shift for efficient screening of fluorinated fragments which are racemates and/or display multiple conformers. Dalvit C, Knapp S. Magn Reson Chem 55 1091-1095 (2017)
  10. Docking rigid macrocycles using Convex-PL, AutoDock Vina, and RDKit in the D3R Grand Challenge 4. Kadukova M, Chupin V, Grudinin S. J Comput Aided Mol Des 34 191-200 (2020)
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  12. Functional insights from targeted imaging BACE1: the first near-infrared fluorescent probe for Alzheimer's disease diagnosis. Bi A, Wu J, Huang S, Li Y, Zheng F, Ding J, Dong J, Xiang D, Zeng W. Biomater Res 26 76 (2022)
  13. Research Support, Non-U.S. Gov't What is the future for fragment-based drug discovery? Keserű GM, Hann MM. Future Med Chem 9 1457-1460 (2017)
  14. Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies. Wang Y, Yang F, Yan D, Zeng Y, Wei B, Chen J, He W. Molecules 28 4773 (2023)
  15. Practical Considerations and Guidelines for Spectral Referencing for Fluorine NMR Ligand Screening. Ayotte Y, Woo S, LaPlante SR. ACS Omega 7 13155-13163 (2022)


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