The ‘scaffold’ concept is widely applied in medicinal chemistry and drug design to generate, analyze, and compare core structures of bioactive compounds and analog series in a search for new active molecules . This scaffold-based design has been one of the standard approaches in small-molecule drug discovery, where a pharmacophore or a scaffold is first identified based on available data (HTS, phenotypic or target-based screening, in silico molecular modeling, etc.) and then a library of derivative compounds is probed to find those showing optimum potency and selectivity, as well as favorable ADMET profile (hit-to-lead and lead optimization of compound series). Scaffolds are often viewed differently from a chemical and computational perspective, since they can be defined algorithmically or be grounded in medicinal chemistry knowledge.
At Life Chemicals, we have prepared an original stock collection of 193,000 novel small-molecule screening compounds for medicinal chemistry and drug discovery screening projects, using 1580 molecular scaffolds (including 400 premium ones). Our cheminformatics team has performed scaffold selection and prioritization, 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 chemical scaffold templates from compound sets [1-3].
Key features of the scaffold database:
- Maximum structural diversity and rare chemotype selection
- Exclusive novelty of all scaffolds and confidently promising compounds verified with patent search (privileged IP position) and confirmed with 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 structure filtering employed to favor drug-like properties
To improve the quality of final compounds, careful design and strict selection of chemically diverse building blocks for scaffold decoration are achieved with the reference to published criteria . Lead-oriented synthesis principles to enhance our HTS Compound Collection with high-quality drug-like screening compounds possessing optimal physicochemical properties are applied .
We provide the synthesis of novel tangible molecules by the decoration of our heterocyclic scaffolds via validated synthetic procedures to meet various customers’ requirements and specifications. Alternatively, custom synthesis of specific compounds or chemical compound libraries based on the customer’s scaffolds or scaffold hopping is available upon request and can be carried out on both FFS and FTE basis.
Additionally, analysis and categorization of any screening library by a chemoinformatics scaffold-based approach (based on 2D fingerprints, similarity, or mathematical models) can be performed to the customer’s order.
Feel free to contact us directly at email@example.com to get additional information, discuss your specific requirements, or place a purchase order.
Explore and purchase our building blocks via our online shop! There you can check compound availability, current prices, and lead time information. The compounds can be searched by CAS, catalog number, substructure, or similarity search.
Figure 1. Example of final compounds designed with the use of molecular scaffolds through the preparation of intermediate building blocks.
- Hu Y, Stumpfe D, Bajorath J. Computational Exploration of Molecular Scaffolds in Medicinal Chemistry. J Med Chem. 2016 May 12;59(9):4062-76. doi: 10.1021/acs.jmedchem.5b01746. Epub 2016 Feb 3. PMID: 26840095.
- 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
- Delbianco M, Bharate P, Varela-Aramburu S, Seeberger PH. Carbohydrates in Supramolecular Chemistry. Chem Rev. 2016;116(4):1693-752.
- 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
- 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