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].

There are four main approaches based on metal chelation principles using different metal-binding groups (Fig. 1) [6]. FBLD using metal-chelating moieties should be particularly suitable for the discovery of novel metalloenzyme inhibitors as chelator agents [1]:

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

We have designed a new Chelator Fragment Library (over 1,580 drug-like fragments) based on the Chelator Focused Library and the Life Chemicals HTS Compound Collection. All the selected compounds 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 the Library. 

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

Figure 2. Representative compounds from the 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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