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Combining NMR and X-ray Crystallography in Fragment-Based Drug Discovery: Discovery of Highly Potent and Selective BACE-1 Inhibitors

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Fragment-Based Drug Discovery and X-Ray Crystallography

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 317))

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.

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Abbreviations

AD:

Alzheimer’s disease

ADMET:

Absorption distribution, metabolism, excretion, and toxicity

APP:

Amyloid precursor protein

Aβ:

Amyloid beta peptides ranging from 37 to 42 amino acids in length

BACE-1:

β-site APP cleaving enzyme

cLogP:

Computed partition coefficient of a compound

CNS:

Central nervous system

c-STD:

Competition saturation transfer difference

FBDD:

Fragment-based drug discovery

FBS:

Fragment-based screening

FQ:

Fit quality

HCS:

High concentration functional screening

HSQC:

Heteronuclear single quantum coherence

HTS:

High-throughput screening

IC50 :

Half maximal inhibitory concentration

ITC:

Isothermal calorimetry

K D :

Equilibrium dissociation constant

K I :

Equilibrium inhibition constant

LE:

Ligand efficiency

LLE:

Ligand lipophilicity efficiency

MW:

Molecular weight

NMR:

Nuclear magnetic resonance

PK:

Pharmacokinetics

SAR:

Structure–activity relationship

SPR:

Surface plasmon resonance

STD:

Saturation transfer difference

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Acknowledgments

We would like to thank Mark McCoy and Jennifer Gesell for their many successful contributions to fragment-based NMR screening and FBDD, and Zhong-Yue Sun, Matthew E. Kennedy, Brian M. Beyer, Mary M. Senior, Elizabeth M. Smith, Terry L. Nechuta, Yuanzan Ye, Jared Cumming, Lingyan Wang, Jesse Wong, Xia Chen, Reshma Kuvelkar, Leonard Favreau, Vincent S. Madison, Michael Czarniecki, Brian A. McKittrick, Eric M. Parker, John C. Hunter, and William J. Greenlee for their invaluable contributions to the BACE-1 work and for their exceptional teamwork, as well as many other colleagues who have contributed to the success of this project over the years.

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Authors and Affiliations

  1. Global Structural Chemistry and Global Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ, 07033, USA

    Daniel F. Wyss, Yu-Sen Wang, Hugh L. Eaton, Corey Strickland, Johannes H. Voigt, Zhaoning Zhu & Andrew W. Stamford

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  1. Daniel F. Wyss
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  2. Yu-Sen Wang
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  3. Hugh L. Eaton
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  4. Corey Strickland
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  5. Johannes H. Voigt
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  6. Zhaoning Zhu
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  7. Andrew W. Stamford
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Correspondence to Daniel F. Wyss .

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  1. Astex Pharmaceuticals, Milton Road, Cambridge, CB4 0QA, United Kingdom

    Thomas G. Davies

  2. , Department of Biochemistry, University of Cambridge, Tennis Court Road 80, Cambridge, CB2 1GA, United Kingdom

    Marko Hyvönen

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© 2011 Springer-Verlag Berlin-Heidelberg

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Wyss, D.F. et al. (2011). Combining NMR and X-ray Crystallography in Fragment-Based Drug Discovery: Discovery of Highly Potent and Selective BACE-1 Inhibitors. In: Davies, T., Hyvönen, M. (eds) Fragment-Based Drug Discovery and X-Ray Crystallography. Topics in Current Chemistry, vol 317. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2011_183

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