Drug Discovery

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process of discovering new drug candidates. Currently, drug discovery relies on extensive screening of chemical libraries against various extracellular and intracellular molecular targets to find novel chemotypes with the desired action mode. The emergence of click chemistry has greatly facilitated the overall drug discovery process, providing convenience for the synthesis of the building blocks of new molecular entities (NMEs)^[1]. Click chemistry-based drug discovery can be classified into three parts: (i) high-throughput screening (HTS); (ii) fragment-based drug discovery (FBDD); and (iii) dynamic template-assisted strategies in FBDD. Details are described in the applications.

Applications

• High-throughput screening (HTS)

Click chemistry plays a crucial role in HTS. Small molecule libraries assembled using click chemistry have been successfully employed in generating unique inhibitor and activity-based fingerprints of important enzymes^[2]. In addition, Kitamura et al^[3]. relied on the SuFEx click reaction between iminosulfur oxydifluoride (RN=S(O)F₂) cores and primary or secondary amines to create a focused library of compounds united by sulfamide bonds (Scheme 1), which accelerates the development of robust biological probes and drug candidates.

Scheme 1. Lead molecules can be assembled through SuFEx click reaction
between iminosulfur oxydifluoride (RN=S(O)F₂) cores and primary or
secondary amines to generate a diversified library.

• Fragment-based drug discovery (FBDD)

FBDD also known as fragment-based lead discovery (FBLD) is a method used for finding lead compounds as part of the drug discovery process and the fragments are small organic molecules with small size and low molecular weight. Click chemistry is one of the most practical methods for the development of fragment-based inhibitors due to its highly modular and efficient reactive nature. The assembled products could be screened directly for inhibition without purification because of the efficiency and water-compatible nature of click chemistry .

• Dynamic template-assisted strategies in FBDD

There is a major challenge of FBDD: identification of low-affinity fragments as well as efficient and biologically active linkages of the fragments. In order to solve this problem, researchers proposed dynamic template-assisted strategies. These strategies use a target protein as a template for selection and/or assembly of optimal fragment combinations. In addition, all dynamic template-assisted strategies share a common chemical reaction, which can be reversible or irreversible and enzymatic or non-enzymatic, for the detection of the best fragment combination. The most widely used reaction for dynamic template-assisted strategies is so-called in situ click chemistry. With the help of in situ click chemistry, pharmaceutical compositions of closely related but fragmented prodrugs can be designed to specifically interact with molecular targets, such as proteins or genes, allowing personalized therapy.

What Can We Do?

Alfa Chemistry has a strong research foundation in the field of drug discovery. We have ability to help you explore the various applications of click chemistry and provide you with related click chemistry reagents, technical advice and services. If you have problems, please don't hesitate to contact us.

References

1. Meghani, N.M.; et al. Mechanistic applications of click chemistry for pharmaceutical drug discovery and drug delivery. Drug Discovery Today. 2017, 11(22): 1604-1619.
2. Niphakis, M.J.; Cravatt, B.F. Enzyme inhibitor discovery by activity-based protein profiling. Annual Review of Biochemistry. 2014, 83: 341-377.
3. Kitamura, S.; et al. SuFEx-enabled high-throughput medicinal chemistry. Journal of the American Chemical Society. 2020, 25(142): 10899-10904.