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Chelator Fragment Library

Fragment-based lead design (FBLD), sometimes referred to as fragment-based drug discovery (FBDD), is an increasingly important strategy for discovery of biologically active compounds [1]. The application of FBLD to metalloprotein targets of medicinal interest has been described in the literature [1-3]. Nonetheless, the design, synthesis, and use of fragment libraries based on metal chelators for FBLD applications have not been studied extensively in spite of the fact that they are of great scientific interest. Several small-molecule chelators were shown to effectively inhibit metalloproteins associated with many diseases such as cancer, inflammatory, infectious, cardiovascular, neurodegenerative and other diseases [1,4,5].

At Life Chemicals, we have designed a new Chelator Fragment Library of about 1,600 drug-like chelating fragments.

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

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Compound selection

There are four main approaches based on metal chelation principles using different metal-binding groups (Fig. 1) [6]:

  1. redistributing a metal across biological membranes via formation of neutral, lipophilic complexes
  2. inactivating an enzyme active site by taking advantage of metal chelation to form protein-metal-chelator ternary complexes
  3. enhancing the reactivity of a metal by forming a chelate complex, for example that promotes redox cycling and generation of reactive oxygen species or other cytotoxic products
  4. inactivating the reactivity of a metal, for example by forming a chelate complex that prevents Fenton chemistry where redox cycling catalyzes formation of reactive oxygen species

FBLD using metal-chelating moieties should be particularly suitable for the discovery of novel metalloenzyme inhibitors as chelator agents [1]:

  • Demonstrate typically high binding affinities
  • Provide a diverse range of molecular platforms
  • Their propensity to bind metal ions allows better prediction of their probable binding position within a protein active site in the absence of experimental structural data of the complex

This Screening Set is based on the Life Chemicals Chelator Focused Screening Libraryas well as the HTS Compound Collection and General Fragment Library. All the selected fragment-like compounds with potential chelating action have passed a number of substructure, similarity, and physicochemical property filters and were narrowed down according to an expanded Lipinski’s Rule of Three. All compounds containing toxic, bad, and reactive groups have been filtered out from this Screening Library.

Physicochemical parameters are summarized in the table below:

ParameterValue Average
MW < 300 207.6
cLogP < 3 1.2
RotBonds ≤ 3 1.9
Donors ≤ 3 1.3
Acceptors ≤ 3 2.5
TPSA < 140 68.5
Rings 0-5 1.9
LogSw > -6 -2.3

 

Various approaches that use principles of metal chelation. Picture adapted from Franz, K. J. et al., 2013

Figure 1. Various approaches that use principles of metal chelation. Picture adapted from Franz, K. J. et al., 2013 [6]

 

Representative compounds from Chelator Fragment Library

References

  1. Arpita Agrawal, Sherida L. Johnson, Jennifer A. Jacobsen, Melissa T. Miller, Li-Hsing Chen, Maurizio Pellecchia, Seth M. Cohen. Chelator Fragment Libraries for Targeting Metalloproteinases // ChemMedChem. 2010 Feb 1; 5(2): 195–199.
  2. Megan K Thorson, David T Puerta, Seth M Cohen, Amy M Barrios. Inhibition of the Lymphoid Tyrosine Phosphatase: The Effect of zinc(II) Ions and Chelating Ligand Fragments on Enzymatic Activity // Bioorg Med Chem Lett. 2014 Aug 15;24(16):4019-22.
  3. Thais A. Sales, Ingrid G. Prandi, Alexandre A. de Castro, Daniel H. S. Leal, Elaine F. F. da Cunha,1 Kamil Kuca, Teodorico C. Ramalho. Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments // Int J Mol Sci. 2019 Apr; 20(8): 1829.
  4. Jennifer A. Jacobsen, Jessica Fullagar, Melissa T. Miller, and Seth M. Cohen. Identifying Chelators for Metalloprotein Inhibitors Using a Fragment-Based Approach // J Med Chem. 2011 Jan 27; 54(2): 591–602.
  5. Katherine J. Franz. Clawing Back: Broadening the Notion of Metal Chelators in Medicine // Curr Opin Chem Biol. 2013 Apr; 17(2): 143–149.
  6. Franz, K. J. Clawing Back: Broadening the Notion of Metal Chelators in Medicine. Curr. Opin. Chem. Biol. 2013, 17 (2), 143–149. 
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