What is chemical genomics?
In chemical genomics, a library of small compounds is used to treat cells or whole organisms in chemical well plates. The goal of this approach is to investigate molecular pathways and to determine if any small compounds in the chemical library have the ability to rescue mutant phenotypes [1, 2]. Additionally, chemical genomics provides insight into potential therapeutics for diseases [2].
Figure 1. Depicts the process of a chemical screen. In this instance, embryos are placed in wells and treated with chemicals. The embryos are screened to determine if there was an alteration to their phenotype.
There are two different types of libraries that can be selected when performing a chemical screen: a diversity-based library or a target-focused library. A diversity-based library includes more of a general approach, in which a wider variety of chemical compounds are used for screening. In turn, the outcomes of this screening can lead to insight on further steps for more chemical screens in the future [3]. A target-focused library includes a particular collection of compounds intended to target a specific protein or an associated family of targets [4].
Additionally, there are two types of screens that can be performed: a forward screen or a reverse screen. In a reverse screen, a biochemical assay is performed to determine if there are compounds that are able to modify "the activity of a purified target protein of interest" [5]. In a forward screen, assays are performed and phenotypes are observed to determine if any phenotypic changes occurred a result of treatment with a chemical compound from the library [5].
Additionally, there are two types of screens that can be performed: a forward screen or a reverse screen. In a reverse screen, a biochemical assay is performed to determine if there are compounds that are able to modify "the activity of a purified target protein of interest" [5]. In a forward screen, assays are performed and phenotypes are observed to determine if any phenotypic changes occurred a result of treatment with a chemical compound from the library [5].
Figure 2. Displays the workflow of a reverse chemical screen compared to a forward chemical screen.
Have any small molecules been found to bind to GBA1?
PubChem shows that four small molecules have been found to bind to GBA1:
Discussion
Four small molecules have been found to bind to GBA1 [6]. Gaucher disease has treatments such as enzyme replacement therapy. However, the neurological symptoms of this disease are not receptive to this treatment because the enzyme struggles to cross the blood-brain barrier [7]. Small molecular chaperones, which can help with protein folding and transmission, serve as another possibility for Gaucher disease treatments [8]. In the past, proposed chaperones have been inhibitory in nature, which means that they may run the risk of hindering enzymatic activity [8]. ML198 and ML266 (shown above), on the other hand, are non inhibitory chaperones [8]. As a result, ML198 and ML266 are worth consideration when it comes to designing a target-focused library for studying Gaucher disease.
References
1. Asad, Z., & Sachidanandan, C. (2020). Chemical screens in a zebrafish model of CHARGE syndrome identifies small molecules that ameliorate disease-like phenotypes in embryo. European journal of medical genetics, 63(2), 103661. https://doi.org/10.1016/j.ejmg.2019.04.018
2. Dang, M., Fogley, R., Zon, L.I. (2016). Identifying Novel Cancer Therapies Using Chemical Genetics and Zebrafish. In: Langenau, D. (eds) Cancer and Zebrafish. Advances in Experimental Medicine and Biology, vol 916. Springer, Cham. https://doi.org/10.1007/978-3-319-30654-4_5
3. Golub, A. (2020, January 28). Diversity-based Screening of Compound Libraries in Drug Discovery. Life Chemicals. Retrieved May 5, 2023, from https://lifechemicals.com/blog/computational-chemistry/diversity-based-screening-of-compound-libraries-in-drug-discovery#:~:text=The%20diversity%2Dbased%20library%20design,1).
4. Harris, C. J., Hill, R. D., Sheppard, D. W., Slater, M. J., & Stouten, P. F. (2011). The design and application of target-focused compound libraries. Combinatorial chemistry & high throughput screening, 14(6), 521–531. https://doi.org/10.2174/138620711795767802
5. Markossian, S., Ang, K. K., Wilson, C. G., & Arkin, M. R. (2018). Small-Molecule Screening for Genetic Diseases. Annual Review of Genomics and Human Genetics, 19(1), 263–288. https://doi.org/10.1146/annurev-genom-083117-021452
6. Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2023). PubChem 2023 update. Nucleic Acids Res., 51(D1), D1373–D1380. https://doi.org/10.1093/nar/gkac956
7. Gaucher Basics. Childrens Gaucher Research Fund. (n.d.). Retrieved April 22, 2023, from https://www.childrensgaucher.org/about-gaucher/gaucher-basics/
8. Rogers S, Patnaik S, Schoenen F, et al. Discovery, SAR, and Biological Evaluation of Non-inhibitory Chaperones of Glucocerebrosidase. 2012 Mar 27 [Updated 2013 Mar 7]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK143537/
2. Dang, M., Fogley, R., Zon, L.I. (2016). Identifying Novel Cancer Therapies Using Chemical Genetics and Zebrafish. In: Langenau, D. (eds) Cancer and Zebrafish. Advances in Experimental Medicine and Biology, vol 916. Springer, Cham. https://doi.org/10.1007/978-3-319-30654-4_5
3. Golub, A. (2020, January 28). Diversity-based Screening of Compound Libraries in Drug Discovery. Life Chemicals. Retrieved May 5, 2023, from https://lifechemicals.com/blog/computational-chemistry/diversity-based-screening-of-compound-libraries-in-drug-discovery#:~:text=The%20diversity%2Dbased%20library%20design,1).
4. Harris, C. J., Hill, R. D., Sheppard, D. W., Slater, M. J., & Stouten, P. F. (2011). The design and application of target-focused compound libraries. Combinatorial chemistry & high throughput screening, 14(6), 521–531. https://doi.org/10.2174/138620711795767802
5. Markossian, S., Ang, K. K., Wilson, C. G., & Arkin, M. R. (2018). Small-Molecule Screening for Genetic Diseases. Annual Review of Genomics and Human Genetics, 19(1), 263–288. https://doi.org/10.1146/annurev-genom-083117-021452
6. Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2023). PubChem 2023 update. Nucleic Acids Res., 51(D1), D1373–D1380. https://doi.org/10.1093/nar/gkac956
7. Gaucher Basics. Childrens Gaucher Research Fund. (n.d.). Retrieved April 22, 2023, from https://www.childrensgaucher.org/about-gaucher/gaucher-basics/
8. Rogers S, Patnaik S, Schoenen F, et al. Discovery, SAR, and Biological Evaluation of Non-inhibitory Chaperones of Glucocerebrosidase. 2012 Mar 27 [Updated 2013 Mar 7]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK143537/
Links to Images
Cover Image: https://www.alamy.com/stock-photo-chemistry-science-chemical-elements-105167258.html
Figure 1: https://link.springer.com/chapter/10.1007/978-3-319-30654-4_5#citeas
Figure 2: https://www.annualreviews.org/doi/10.1146/annurev-genom-083117-021452
Image of small molecules that have been shown to bind to GBA1: https://pubchem.ncbi.nlm.nih.gov/
Figure 1: https://link.springer.com/chapter/10.1007/978-3-319-30654-4_5#citeas
Figure 2: https://www.annualreviews.org/doi/10.1146/annurev-genom-083117-021452
Image of small molecules that have been shown to bind to GBA1: https://pubchem.ncbi.nlm.nih.gov/