Scaffolds and Scaffold-based Compounds

Life Chemicals offers its original stock collection of 140,000 novel small-molecule screening compounds based on 1,300 novel molecular scaffolds (including more than 500 premium ones) for medicinal chemistry and drug discovery screening projects.

Scaffold selection and prioritization are performed by means of organic and analytical chemistry approaches (reaction-oriented scaffold design) where chemical scaffolds are viewed as structural cores with several diversity points. Their chemical modifications result in a number of intermediates/building blocks, subsequent functionalization/decoration of which provide final compounds (Fig. 1). Retrosynthetic rules can be applied to isolate synthetically relevant scaffolds from compound sets [1-3].

Key features of the scaffold database:

  • Maximum structural diversity and rare chemotypes selection
  • The novelty for all scaffolds and potentially promising compounds verified with patent search (privileged IP position) and similarity to molecules included in the eMolecules database
  • The number of variation points kept within 2-3 per scaffold, preference given to structures with one variation point per cycle
  • Several structural physicochemical filters applied (modified Lipinski and Veber rules, etc.)
  • In-house MedChem structures filtering also employed

In order to improve the quality of final compounds, careful design, and strict selection of chemically diverse building blocks for scaffold decoration are performed with the reference to published criteria [1]. Lead-oriented synthesis principles to enhance our HTS Compound Collection with high-quality drug-like screening compounds possessing optimal physicochemical properties are applied [4].

We provide synthesis of novel tangible molecules by decoration of our scaffolds via validated synthetic procedures to meet various customer’s requirements and specifications. Alternatively, custom synthesis of specific compounds or chemical compound libraries based on customer’s scaffolds or scaffold hopping is available upon request, performed on both FFS and FTE base.

Additionally, we offer analysis and categorization of any screening library by a chemoinformatics scaffold-based approach (based on 2D fingerprints, similarity, or mathematical models) on request.

 Example of final compounds designed with the use of molecular scaffolds through the preparation of intermediate building blocks

Figure 1. Example of final compounds designed with the use of molecular scaffolds through the preparation of intermediate building blocks.

References

  1. Goldberg FW, Kettle JG, Kogej T, Perry MW, Tomkinson NP. Designing novel building blocks is an overlooked strategy to improve compound quality. Drug Discov Today. 2015;20(1):11-17. doi:10.1016/j.drudis.2014.09.023
  2. Delbianco M, Bharate P, Varela-Aramburu S, Seeberger PH. Carbohydrates in Supramolecular Chemistry. Chem Rev. 2016;116(4):1693-752.
  3. Sadek KU, Mekheimer RA, Abd-Elmonem M, Elnagdi MH. Aroyl and acyl cyanides as orthogonal protecting groups or as building blocks for the synthesis of heterocycles. Mol Divers. 2019;23(4):1065-1084. doi:10.1007/s11030-019-09915-w
  4. Nadin A., Hattotuwagama Ch., Churcher I. Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry. Angew. Chem. Int. Ed. 2012, 51, 1114–1122. doi: 10.1002/anie.201105840