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 [1]. 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.). Then a library of derivative compounds is screened to identify those with optimal potency and selectivity, as well as a favorable ADMET profile (hit-to-lead and lead optimization of the compound series). Scaffolds are often viewed differently from chemical and computational perspectives, since they can be defined algorithmically or grounded in medicinal chemistry knowledge.
At Life Chemicals, we have prepared an original stock collection of over 230,000 novel small-molecule screening compounds for medicinal chemistry and drug discovery screening projects, using 1300 molecular scaffolds (including 400 premium ones). Our cheminformatics team has performed scaffold selection and prioritization on the basis of organic and analytical chemistry approaches (reaction-oriented scaffold design), by which chemical scaffolds are viewed as structural cores with multiple diversity points. Their chemical modifications yield several intermediates/building blocks whose subsequent functionalization/decoration provides final compounds (Fig. 1). Retrosynthetic rules can be applied to isolate synthetically relevant chemical scaffold templates from compound sets [1-3].
Our Mini Scaffold Library comprises approximately 2,500 drug-like screening compounds, all built around a distinct core scaffold to ensure broad and well-balanced chemical diversity. Compounds were carefully selected from our proprietary HTS Collection through stringent filters to remove reactive, toxic or otherwise undesirable motifs, including structures associated with promiscuous activity (PAINS), resulting in a high-quality drug-like set.
The Golden Scaffold Library, derived from the same extensive HTS Compound Collection, contains over 5,900 compounds optimized for small-scale high-throughput screening. In this selection, every unique scaffold is adorned by 1–3 strategically varied functional groups, thereby expanding local chemical space while still maintaining efficiency. This design maximizes screening success rates by combining focused diversity with practical library size.
Feel free to contact us directly at orders@lifechemicals.com for additional information, to discuss your specific requirements or to place a purchase order.
Explore and purchase our building blocks via our online shop! Check compound availability, current prices and lead time information. The compounds can be searched by CAS number, catalog number, substructure or 2D similarity.
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Figure 1. Example of final compounds designed with the use of molecular scaffolds.
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
- Structural physicochemical filters (modified Lipinski and Veber rules, etc.) applied
- In-house MedChem structure filtering to favor drug-like properties
To improve the quality of the final compounds, careful design and strict selection of chemically diverse building blocks for scaffold decoration are guided by well-established published criteria [1]. To enhance our HTS Compound Collection with high-quality drug-like screening compounds possessing optimal physicochemical properties, lead-oriented synthesis principles are applied [4].
Customized synthesis approach
We provide the synthesis of novel tangible molecules by decorating our heterocyclic scaffolds using 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. It can be carried out on both an FFS and an FTE basis.
Additionally, analysis and categorization of any screening library using a cheminformatics scaffold-based approach (based on 2D fingerprints, similarity, or mathematical models) can be performed at the customer’s request.
References
- 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. C