The notion of chirality, first introduced by Lord Kelvin in 1894, pertains to a fundamental property of asymmetry that distinguishes systems that are non-superimposable mirror images of each other. Chiral properties of matter manifest themselves in various areas and scientific disciplines, spanning from particle physics and life sciences to our understanding of the topology of the cosmos (Fig. 1). Chiral media have become one of the foci of modern physics, chemistry, and materials science since they exhibit extraordinary optical, biochemical, and pharmaceutical properties [1-3].
Figure 1. From [1]. Chirality in nature at various scales, from enantiomeric molecules at the sub-nanometer scale to DNA and enzymes at the nanometer scale to living systems and galaxies at the macroscopic scale.
The concept of chirality plays a pivotal role in the intricate world of drug design and development [4,5]. Chiral mirror-image molecules – nantiomers – can exhibit dramatically different pharmacologic behaviors while sharing the same chemical composition. The difference arises from the distinctive interactions of enantiomers with chiral biological receptors, enzymes, and other biomolecules. As follows, enantiomers often demonstrate varying degrees of biological activity, potency, and side effects, which are crucial factors for designing drugs that are not only effective but also safe. For instance, worth mentioning is a tragic example of thalidomide [6], one enantiomer of which alleviated morning sickness during pregnancy. At the same time, its mirror-image counterpart causes severe congenital disabilities, highlighting the importance of considering chirality in drug design to minimize unwanted side effects and maximize therapeutic efficacy.
Chirality and stereochemistry of molecules are crucial issues to be taken into account in high-throughput screening (HTS) testing for drug discovery. On the one hand, they are associated with good opportunities; however, on the other hand, they introduce certain challenges.
Vivid advantages offered by HTS when it comes to chiral compounds are as follows:
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increased sensitivity: HTS can detect even subtle differences in the biological activity of enantiomers, providing insights into their pharmacologic profiles;
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rapid screening: HTS accelerates the evaluation of chiral compounds, expediting drug development processes;
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relative cost-efficiency: the possibility to test multiple enantiomers simultaneously reduces expenses compared to traditional methods.
While HTS does accelerate drug discovery, among its negative aspects are chiral compound cost, the problem of separation, and regulatory compliance [4-5,7]:
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compound cost: producing enantiomerically pure compounds can be expensive due to the need for specialized techniques and reagents;
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separation challenges: separating enantiomers for individual testing in HTS can be a complex and time-consuming task;
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regulatory restrictions: regulatory authorities often require rigorous evaluation of enantiomers, leading to extended approval timelines.
To sum up the above, tackling the first isolation of enantiomers, we must also ensure that enantiomeric purity complies with relevant pharmacological standards (Fig 2). Finally, the cost of isolation can be a substantial burden on drug development budgets as its techniques, namely chiral chromatography and asymmetric synthesis, demand specialized expertise and resources.
Figure 2. Advantages of the use of single enantiomer drugs.Adopted from [4].
Despite existing stumbling blocks, small-molecule chirality is a promising avenue for a wide range of technologies. In the R&D of pharmaceuticals, small-molecule chirality makes possible fine-tuning of drug potency, selectivity, and safety profiles, enabling the design of more effective therapies with fewer side effects [4-5, 7-9]. Additionally, chiral small molecules serve as essential building blocks in medicinal chemistry, facilitating the synthesis of complex drug candidates and enabling access to diverse chemical space.
Beyond pharmaceuticals, small-molecule chirality finds applications in materials science, particularly in the design of functional materials with tailored properties [2]. Chiral molecules contribute to the development of advanced materials, such as liquid crystals, polymers, and organic electronics, where chirality influences optical, mechanical, and electronic characteristics. Moreover, small-molecule chirality plays a vital role in the emerging field of chiral nanotechnology, where precise control over molecular asymmetry is exploited to create novel nanoscale structures and devices. These advances hold potential applications from nanomedicine and biotechnology to information storage and quantum computing [2, 10].
In the pursuit to support the continued research in this interdisciplinary field and unlock new capabilities and applications of its products, Life Chemicals offers a number of proprietary collections of 3D-shaped topologically non-trivial drug-like molecules for the study of stereochemistry and chirality properties:
- 3D Compound Libraries for HTS
- 3D-shaped Fragment Library
- Fsp³-enriched Screening Compound Library
- Fsp³-enriched Fragment Library
In addition, we provide the following services to support the drug design research:
- Quality Control to be performed by our Physicochemical Research Lab: Chiral chromatography and resolution of racemates
- Computational Chemistry performed for specific targets defined by the customer
- Custom Synthesis of compounds ordered by the customer, as well as hit optimization
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Visit our Website for a detailed product description.
Download SD files with compound structures directly from our Downloads section
Custom compound selection based on specific parameters can be performed on request. Competitive pricing and the most convenient terms are provided.
References
1. Zhang, G., Cheng, X., Wang, Y., Zhang`, W. (2023). Supramolecular chiral polymeric aggregates: Construction and applications. Aggregate, 4:e262. DOI: 10.1002/agt2.262
2. Luk'yanchuk, I., Razumnaya, A., Kondovych, S., Tikhonov, Y., Vinokur, V.M. (2024). Topological ferroelectric chirality. arXiv:2406.19728 https://arxiv.org/abs/2406.19728
3. Wagnière, G. H. On chirality and the universal asymmetry: reflections on image and mirror image. John Wiley & Sons, 2007.
4. Brooks W.H., Guida W.C., Daniel K.G. (2011). The significance of chirality in drug design and development. Curr Top Med Chem. 11(7):760-70. DOI: 10.2174/156802611795165098
5. Ceramella, J.; Iacopetta, D.; Franchini, A.; De Luca, M.; Saturnino, C.; Andreu, I.; Sinicropi, M.S.; Catalano, A. (2022). A Look at the Importance of Chirality in Drug Activity: Some Significative Examples. Appl. Sci. 12:10909. DOI:10.3390/app122110909
6. Blaschke, G. V., Kraft, H. P., Fickentscher, K., & Koehler, F. (1979). Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers (author's transl). Arzneimittel-forschung, 29(10), 1640-1642. PMID: 583234
7. Srinivas, N. R., Barbhaiya, R. H., & Midha, K. K. (2001). Enantiomeric drug development: issues, considerations, and regulatory requirements. Journal of pharmaceutical sciences, 90(9), 1205-1215. DOI: 10.1002/jps.1074
8. Abram, M., Jakubiec, M., Kamiński, K. (2019). Chirality as an Important Factor for the Development of New Antiepileptic Drugs. ChemMedChem 14, 1744. DOI: 10.1002/cmdc.201900367
9. McConathy, J., Owens, M.J. (2003). Stereochemistry in Drug Action. Prim Care Companion J Clin Psychiatry. 5(2):70-73. DOI: 10.4088/pcc.v05n0202
10. Brandt, J., Salerno, F. & Fuchter, M. (2017). The added value of small-molecule chirality in technological applications. Nat Rev Chem 1:0045. DOI: 10.1038/s41570-017-0045
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