Molecular complexity and the presence of chiral centers have been demonstrated to significantly increase the potential of organic compounds to evolve into successful drug candidates. This insight has fueled the demand for advanced screening libraries that feature diverse and complex molecular structures based on sp3-hybridized carbons.
In response to this R&D need, our cheminformatics team has prepared its original selection of over 15,500 poly- and bicyclic small molecules containing spiro, bridged and fused rings, as well as stereogenic centers to cover more advantageous chemical space for phenotypic or target-based screening in drug discovery. It must be emphasized that these novel drug-like screening compounds picked out from our in-house HTS Compound Collection are distinguished by their high chemical and structural diversity.
The library is organized into four distinct subsets:
- Spirocyclic Subset (7,100 compounds)
- Bicyclic Compound Subset (6,000 compounds)
- Polycyclic Compound Subset (2,100 compounds)
- Macrocyclic Compound Subset (250 compounds & custom synthesis)
Spirocyclic Subset
This Subset includes over 7,100 fsp3-rich screening compounds based on carbocyclic and heterocyclic spiro scaffolds. Such 3D-shaped small molecules, characterized by their bicyclic systems joined at a single atom, are becoming increasingly valuable in drug discovery due to their unique structural features. The inherent spiro configuration yields high Fsp3 values, improved physical characteristics compared to flat aromatic systems, and higher rigidity, which reduces conformational entropy and enhances stereospecific interactions with various valuable biological targets, such as receptors, enzymes, and ion channels [1-2]. This novel structural diversity facilitates the design of drugs with innovative mechanisms of action, improved binding affinity, target specificity and optimized pharmacokinetic and pharmacodynamic profiles.
Representative spirocyclic screening compounds
Bicyclic Compound Subset
As the demand for three-dimensional molecular complexity continues to grow, novel complex sp³-rich structures, like bridged and fused rings, are gaining more and more attention in medicinal chemistry and drug discovery. Medium-sized bridged rings are particularly valuable due to their ability to improve pharmacological profile and enable selective, high-affinity binding to biological targets, allowing the exploration of novel chemical space beyond conventional flat architectures in early-stage drug discovery. Such compact structures often offer a balanced lipophilicity profile, supporting lead optimization and enhancing pharmacokinetic properties. In the context of this demand, we offer over 6,000 structurally diverse screening compounds featuring various bridged and fused bicyclic cores, carefully selected from our proprietary HTS Compound Collection.
Representative bicyclic bridged and fused screening compounds
Polycyclic Compound Subset
The lipophilic nature of many polycyclic compounds allows them to efficiently cross biological membranes, enhancing their ability to reach intracellular targets. This property is particularly beneficial for molecules designed to modulate intracellular pathways or interact with intracellular receptors. Additionally, their structural complexity supports the incorporation of diverse functional groups, enabling fine-tuned control over biological activity and selectivity, making them well-suited for tackling tough drug targets. As a result, polycyclic compounds are valuable candidates for drug development across various therapeutic areas, including cancer, infectious diseases, and neurological disorders [3-4].
Our Polycyclic Compound Set features 2,100 tri- and tetracyclic screening compounds with structurally complex cores, providing outstanding opportunities for multifunctional drug design.
Representative polycyclic bridged and fused screening compounds
Macrocyclic Compound Subset
Macrocycles offer enhanced selectivity and binding affinity for complex biological targets, including those with challenging binding sites [5]. They combine diverse functionality and stereochemical complexity within a pre-organized ring structure while maintaining enough flexibility to adapt to target surfaces and optimize binding through induced fit.
Their high sp³-hybridized carbon content increases molecular complexity and raises the fsp³ fraction, contributing to three-dimensional architectures. Incorporating macrocyclic structures into drug candidates can enhance metabolic stability, reduce off-target interactions, and improve blood-brain barrier permeability and bioavailability beyond the Rule of Five. Their rigid yet adaptable conformations support precise target binding while maintaining favorable pharmacokinetic properties [6].
Our Macrocyclic Compound Subset includes 250 stock-available macrocycles, carefully selected for their structural complexity and drug-like potential. Moreover, we offer Custom Synthesis expertise to obtain versatile functionalized macromolecules, such as mectins, calixarenes, sulfonimide-based dendrimers, and resorcinarenes.
Representative macrocyclic screening compounds
References
- Zheng Y. et al. Bioorganic & Medicinal Chemistry Letters, 2014, 24, 16, 3673-3682.
- Chen Y., Xu J., Gao P. Org. Chem. Front., 2024, 11, 508-539.
- Oliver, D.W., Malan, S.F. Med. Chem. Res. 17 2008, 137–151.
- Stockdale TP, Williams CM. Chem Soc Rev. 2015, 44(21), 7737-63.
- Garcia Jimenez D, Poongavanam V, Kihlberg J. J Med Chem. 2023, 66(8), 5377-5396.
- Marsault E, Peterson ML. J Med Chem. 2011, 54(7), 1961-2004.