The Role of Chirality in Drug Design and Delivery: A Comprehensive Review

---

Ashwini A. Aher , Syed Ubaid Razvi , Satish Eknath Bahekar , Mirza Shiraz Baig

Department of Pharmacology, Government Medical College, Chhatrapati Sambhajinagar, Aurangabad, Maharashtra, India

Corresponding Author Email: drsatish3683@gmail.com

DOI : https://doi.org/10.51470/APR.2024.03.02.07

Abstract

Keywords

Download this article as:

---

Introduction

The rotation of plane-polarized light by chiral substances was first observed in 1812 by a French physicist Jean-Baptiste Biot. Chiral chemistry was discovered by Louis Pasteur, a French chemist & biologist, in 1848 by inventing 2 isomers of sodium potassium tartrate (Fig. 1). The term chirality was coined in 1894 by Lord Kelvin, a British mathematician, mathematical physicist and engineer. Chirality or molecular handedness, refers to the property of a molecule that renders it non-superimposable on its mirror image. This property, resulting in the existence of enantiomers, is a cornerstone in the field of pharmaceutical sciences. The two enantiomers of a chiral drug can exhibit markedly different biological activities because of their interactions with chiral biological targets such as enzymes, receptors, and nucleic acids. The importance of chirality in drug design and delivery has been increasingly recognized, particularly as technologies like nanocarriers and asymmetric synthesis have advanced.

1. Importance of Chirality in Biological Systems

Biological systems themselves are chiral, comprising chiral amino acids and sugars that form the building blocks of proteins and DNA. This inherent chirality in biological molecules means that the interaction between a drug and its target can vary dramatically depending on the drug’s chirality. For example, the two enantiomers of a drug may bind differently to an enzyme’s active site, leading to differences in therapeutic effects or side effects(Lupu & Hancu, 2021).

2. Optical Isomerism in Organic Molecules

• 2.1 Fundamentals of Optical Isomerism

Optical Isomerism in Organic Molecules delves into the concept of chirality at a molecular level, focusing on how optical isomerism arises from the presence of chiral centres within organic molecules. This form of stereoisomerism is characterized by the ability of chiral molecules to rotate plane-polarized light in different directions, a property that is exploited in chiral analytical techniques such as polarimetry and circular dichroism(Bock, 1991).

• 2.2 Stereoisomerism and Drug Activity

The activity of a drug is often closely related to its stereochemistry. For example, the S-enantiomer of ibuprofen is responsible for its anti-inflammatory activity, while the R-enantiomer is less active and contributes to the overall pharmacokinetic profile by being converted into the S-enantiomer in vivo(Matji et al., 2020; Vieira et al., 2023).  Ketamine’s rapid antidepressant effects are a major breakthrough, with (R)-ketamine showing promise for stronger, longer-lasting benefits and fewer side effects than (S)-ketamine which is approved as a nasal spray for treatment-resistant depression. Research continues to explore its potential as a future treatment for depression(Jelen et al., 2021). This highlights the importance of controlling stereochemistry during drug synthesis to ensure that the therapeutic enantiomer is produced with high purity.

• 2.3 Analytical Techniques for Chiral Molecules

The study of optical isomerism is supported by a range of analytical techniques designed to separate and characterize chiral molecules. Techniques such as chiral high-performance liquid chromatography (HPLC), chiral gas chromatography (GC), and capillary electrophoresis (CE) are commonly used in both research and industry to ensure the enantiomeric purity of drugs. These techniques are critical for quality control during the manufacturing process and for confirming the stereochemical integrity of the final pharmaceutical product(Abousalih et al., 2021; Lupu & Hancu, 2021). there is a technique to differentiate directly Enantiomer of Drugs and Drug-Like Compounds via Noncovalent Copper−Amino Acid Complexation and Ion Mobility-Mass Spectrometry(Blakley et al., 2024).

• 2.4 Chirality with Bio membrane Models

Chirality significantly influences biological membranes, as demonstrated by the distinct effects of d- and l-menthol, with l-menthol providing a cooling effect and d-menthol causing skin irritation. The study investigated how these optical isomers affect membrane heterogeneity, revealing physical differences in their impact on lipid packing and membrane organization(Gusain et al., 2017).

3. Chirality in Drug Design

• 3.1 The Importance of Enantiomers

The Significance of Chirality in Drug Design and Development highlights the critical role that enantiomers play in pharmacology. Enantiomers can have different, sometimes opposite, effects on the body, which makes the study of chirality essential in drug development. For instance, the notorious case of thalidomide, where one enantiomer had sedative effects while the other caused severe birth defects, underscores the need for careful consideration of chirality in drug design(Fig. 2)(H. Brooks et al., 2011; Tokunaga et al., 2018).

• 3.2 Case Studies in Drug Development

Modern drug development increasingly emphasizes the production of enantiomerically pure drugs. This is evident in the development of drugs like esomeprazole (Nexium), the S-enantiomer of omeprazole, which is more effective in treating acid reflux than the racemic mixture(Asghar et al., 2015). Another example is levofloxacin, the active S-enantiomer of the racemic drug ofloxacin, which exhibits a superior safety profile and enhanced antibacterial activity(Abousalih et al., 2021). The R(+) enantiomers of propranolol and atenolol, despite lacking beta-blocker activity, were found to inhibit the formation of infantile haemangioma (IH) blood vessels and HemSC to endothelial cell differentiation, similar to a known SOX18 inhibitor. This suggests that R(+) enantiomers could be repurposed to improve IH treatment efficacy while reducing side effects(Seebauer et al., 2022).

• 3.3 Regulatory Considerations

Regulatory agencies, such as the FDA and EMA, have established guidelines that require the separate evaluation of each enantiomer during the drug approval process. This ensures that both enantiomers are assessed for efficacy and safety, particularly when one enantiomer is active and the other is not, or when both enantiomers have different pharmacological profiles. The development of chiral drugs is thus not only a scientific challenge but also a regulatory necessity(H. Brooks et al., 2011; McVicker & O’Boyle, 2024).

• 3.4 Advances in Asymmetric Synthesis

Advances in asymmetric synthesis have been instrumental in enabling the production of enantiomerically pure drugs. Techniques such as chiral catalysis and the use of chiral auxiliaries have made it possible to selectively synthesize one enantiomer over the other, thereby improving the efficiency and reducing the cost of drug production. These methods are now widely used in the pharmaceutical industry to produce a variety of chiral drugs, including antiretrovirals, antihypertensives, and anticancer agents(Hanke et al., 2020; Jeon et al., 2023; Toenjes & Gustafson, 2018).

4. Chirality in Nanocarrier Drug Delivery

• 4.1 Overview of Graphene Nanocarriers

Graphene-based nanomaterials have emerged as a novel platform in drug delivery, offering advantages such as high surface area, tuneable functionalization, and biocompatibility.It explored how the incorporation of chirality into graphene nanocarriers can improve drug delivery efficiency. Graphene’s planar structure allows it to be functionalized with a variety of chemical groups, including those that introduce chirality(Suzuki et al., 2016).

• 4.2 Chirality-Enhanced Transport

Some studies demonstrated that chirality in graphene nanocarriers significantly enhanced their ability to target and penetrate tumour-like spheroids, which are three-dimensional models that mimic the architecture of solid tumours. The chiral nanocarriers are considered to improve interactions with cellular membranes, facilitating more efficient drug uptake and distribution within the tumour spheroids. This finding aligns with broader research showing that chiral molecules often have enhanced interactions with biological membranes due to the chiral nature of membrane lipids and proteins (Fig. 3).

• 4.3 Implications for Targeted Cancer Therapy

The implications of this study for targeted cancer therapy are significant. Traditional cancer treatments, such as chemotherapy, often lack specificity, leading to systemic toxicity and adverse side effects. Chiral nanocarriers like those studied here offer a promising alternative by enhancing the selective delivery of chemotherapeutic agents directly to tumour cells, thereby increasing the therapeutic index and reducing off-target effects(H. Brooks et al., 2011; Jeon et al., 2023; Suzuki et al., 2016).

• 4.4 Broader Applications of Chiral Nanocarriers

Beyond cancer therapy, chiral nanocarriers are being explored for their potential in treating a range of other diseases, including neurodegenerative disorders, where targeted delivery to specific brain regions could improve therapeutic outcomes. The use of chirality to enhance drug delivery is part of a broader trend towards personalized medicine, where treatments are tailored to the specific genetic and molecular profile of the patient(Jeon et al., 2023).

5. Comparative Analysis and Discussion

• 5.1 Integrating Chirality in Drug Delivery Systems

The findings from the three articles converge on the theme that chirality is an essential consideration in both drug design and delivery. The incorporation of chirality into drug delivery systems, as demonstrated by the graphene nanocarrier study, represents a significant advancement in achieving targeted drug delivery. The selective interaction of chiral nanocarriers with biological membranes can lead to more effective drug delivery, particularly in challenging therapeutic areas such as oncology and neurology(Jeon et al., 2023).

• 5.2 Challenges in Chiral Drug Development

Despite the clear benefits, the development of chiral drugs and drug delivery systems is not without challenges. The synthesis of enantiomerically pure compounds can be technically demanding and costly, requiring advanced techniques in asymmetric synthesis and chiral resolution. Additionally, the regulatory landscape for chiral drugs is complex, with stringent requirements for demonstrating the safety and efficacy of each enantiomer. As research continues, there is a need for further innovations in chiral synthesis and analysis to overcome these challenges and fully realize the potential of chirality in pharmaceutical development(H. Brooks et al., 2011; Toenjes & Gustafson, 2018).

• 5.3 Future Directions

Looking ahead, the integration of chirality into drug development and delivery will likely become even more prominent as personalized medicine advances. Tailoring drugs not only to the genetic profile of the patient but also to the chiral specificity of their biological targets could lead to more effective and safer. Also, DNA oligonucleotides as chiral selectors in capillary electrophoresis, are foundto have enantioselective properties. Remarkably, a combination of three sequences resolved around 20 racemates, showcasing the broad analyte selectivity of nucleic acid-based chiral separation tools for the first time(Tohala et al., 2015).

6. Conclusion

Chirality is a critical factor in drug design and delivery, influencing the pharmacokinetics, pharmacodynamics, and overall therapeutic potential of pharmaceutical compounds. The studies reviewed in this article demonstrate the importance of considering chirality not only in the design of new drugs but also in the development of advanced drug delivery systems. As research in nanotechnology and stereochemistry advances, the integration of chirality into drug delivery systems like graphene nanocarriers promises to enhance the precision and effectiveness of future therapeutics.

7. References

1. Abousalih, F. Z., Karbane, M. E., Echerfaoui, F., Benchekroun, Y. H., Karrouchi, K., Azougagh, M., Bouchafra, H., & Bouatia, M. (2021). Optimization of a Ligand Exchange Chromatography Method for the Enantioselective Separation of Levofloxacin and Its Chiral Impurity. Journal of AOAC INTERNATIONAL, 104(6), 1690–1697. https://doi.org/10.1093/jaoacint/qsab077

2. Asghar, W., Pittman, E., & Jamali, F. (2015). Comparative efficacy of esomeprazole and omeprazole: Racemate to single enantiomer switch. DARU Journal of Pharmaceutical Sciences, 23(1), 50. https://doi.org/10.1186/s40199-015-0133-6

3. Blakley, B. K., Zlibut, E., Gupta, R. M., May, J. C., & McLean, J. A. (2024). Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper–Amino Acid Complexation and Ion Mobility-Mass Spectrometry. Analytical Chemistry, 96(31), 12892–12900. https://doi.org/10.1021/acs.analchem.4c02710

4. Bock, G. (Ed.). (1991). Biological asymmetry and handedness: Symposium …, held at the Ciba Foundation, London 20 – 22 February 1991. Symposium on Biological Asymmetry and Handedness, Chichester. Wiley.

5. Gusain, P., Ohki, S., Hoshino, K., Tsujino, Y., Shimokawa, N., & Takagi, M. (2017). Chirality-Dependent Interaction of d- and l-Menthol with Biomembrane Models. Membranes, 7(4), 69. https://doi.org/10.3390/membranes7040069

6. H. Brooks, W., C. Guida, W., & G. Daniel, K. (2011). The Significance of Chirality in Drug Design and Development. Current Topics in Medicinal Chemistry, 11(7), 760–770. https://doi.org/10.2174/156802611795165098

7. Hanke, N., Türk, D., Selzer, D., Wiebe, S., Fernandez, É., Stopfer, P., Nock, V., & Lehr, T. (2020). A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug–Drug Interaction Studies. Pharmaceutics, 12(6), 556. https://doi.org/10.3390/pharmaceutics12060556

8. Jelen, L. A., Young, A. H., & Stone, J. M. (2021). Ketamine: A tale of two enantiomers. Journal of Psychopharmacology, 35(2), 109–123. https://doi.org/10.1177/0269881120959644

9. Jeon, H., Zhu, R., Kim, G., & Wang, Y. (2023). Chirality-Enhanced Transport and Drug Delivery of Graphene Nanocarriers to Tumor-like Cellular Spheroid. https://doi.org/10.1101/2023.06.27.546698

10. Lupu, D., & Hancu, G. (2021). Achiral and chiral analysis of duloxetine by chromatographic and electrophoretic methods, a review on the separation methodologies. Biomedical Chromatography, 35(1), e4883. https://doi.org/10.1002/bmc.4883

11. Matji, A., Vargas, E., Carvajal, L., Terleira, A. I., Portolés, A., Garcia‐Arieta, A., Torrado, J. J., & Serrano, D. R. (2020). Effect of enantiomerism on the bioequivalence of a new ibuprofen 600‐mg tablet formulation obtained by roller compaction. Chirality, 32(2), 185–190. https://doi.org/10.1002/chir.23148

12. McVicker, R. U., & O’Boyle, N. M. (2024). Chirality of New Drug Approvals (2013–2022): Trends and Perspectives. Journal of Medicinal Chemistry, 67(4), 2305–2320. https://doi.org/10.1021/acs.jmedchem.3c02239

13. Seebauer, C. T., Graus, M. S., Lan Huang, McCann, A., Wylie-Sears, J., Fontaine, F., Karnezis, T., Zurakowski, D., Staffa, S. J., Meunier, F., Mulliken, J. B., Bischoff, J., & Francois, M. (2022). Non–beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma. Journal of Clinical Investigation, 132(3), e151109. https://doi.org/10.1172/JCI151109

14. Suzuki, N., Wang, Y., Elvati, P., Qu, Z.-B., Kim, K., Jiang, S., Baumeister, E., Lee, J., Yeom, B., Bahng, J. H., Lee, J., Violi, A., & Kotov, N. A. (2016). Chiral Graphene Quantum Dots. ACS Nano, 10(2), 1744–1755. https://doi.org/10.1021/acsnano.5b06369

15. Toenjes, S. T., & Gustafson, J. L. (2018). Atropisomerism in Medicinal Chemistry: Challenges and Opportunities. Future Medicinal Chemistry, 10(4), 409–422. https://doi.org/10.4155/fmc-2017-0152

16. Tohala, L., Oukacine, F., Ravelet, C., & Peyrin, E. (2015). Chiral Resolution Capabilities of DNA Oligonucleotides. Analytical Chemistry, 87(11), 5491–5495. https://doi.org/10.1021/acs.analchem.5b01252

17. Tokunaga, E., Yamamoto, T., Ito, E., & Shibata, N. (2018). Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers. Scientific Reports, 8(1), 17131. https://doi.org/10.1038/s41598-018-35457-6

18. Vieira, S. F., Araújo, J., Gonçalves, V. M. F., Fernandes, C., Pinto, M., Ferreira, H., Neves, N. M., & Tiritan, M. E. (2023). Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids. International Journal of Molecular Sciences, 24(12), 10357. https://doi.org/10.3390/ijms241210357