Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan;101(1):103-119.
doi: 10.1111/cbdd.14126. Epub 2022 Aug 9.

Searching for new mTOR kinase inhibitors: Analysis of binding sites and validation of docking protocols

Dorota Stary  1   2   3 , Eugenie Nepovimova  2 , Kamil Kuca  2 , Marek Bajda  1   2
Affiliations

Searching for new mTOR kinase inhibitors: Analysis of binding sites and validation of docking protocols

Dorota Stary et al. Chem Biol Drug Des. 2023 Jan.

Abstract

The mammalian target of rapamycin (mTOR) is an important biological target for development of novel anticancer drugs and potential antiageing agents. Therefore, many scientific groups search for mTOR kinase inhibitors. Herein, we present structure-based approach which could be helpful in the studies on new bioactive compounds. Method validation was preceded by structural analysis of ATP catalytic cleft and FRB domain. In silico studies allowed us to point crucial amino acid residues for ligand binding and develop optimal docking protocols. The presented methodology could be applied for design and development of potential mTOR kinase inhibitors.

Keywords: ATP-binding site; FRB domain; docking validation; inhibitors; mTOR kinase; protein structure analysis.

PubMed Disclaimer

References

REFERENCES

    1. Anandapadamanaban, M., Masson, G. R., Perisic, O., Berndt, A., Kaufman, J., Johnson, C. M., Santhanam, B., Rogala, K. B., Sabatini, D. M., & Williams, R. L. (2019). Architecture of human rag GTPase heterodimers and their complex with mTORC1. Science, 366(6462), 203-210. https://doi.org/10.1126/science.aax3939
    1. Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., Yurova, M. N., Rosenfeld, S. V., & Blagosklonny, M. V. (2011). Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle, 10(24), 4230-4236. https://doi.org/10.4161/cc.10.24.18486
    1. Aylett, C. H. S., Sauer, E., Imseng, S., Boehringer, D., Hall, M. N., Ban, N., & Maier, T. (2016). Architecture of human mTOR complex 1. Science, 351(6268), 48-52. https://doi.org/10.1126/science.aaa3870
    1. Beaufils, F., Cmiljanovic, N., Cmiljanovic, V., Bohnacker, T., Melone, A., Marone, R., Jackson, E., Zhang, X., Sele, A., Borsari, C., Mestan, J., Hebeisen, P., Hillmann, P., Giese, B., Zvelebil, M., Fabbro, D., Williams, R. L., Rageot, D., & Wymann, M. P. (2017). 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a potent, brain-penetrant, orally bioavailable, pan-class i PI3K/mTOR inhibitor as clinical candidate in oncology. Journal of Medicinal Chemistry, 60(17), 7524-7538. https://doi.org/10.1021/acs.jmedchem.7b00930
    1. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., & Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28(1), 235-242. https://doi.org/10.1093/nar/28.1.235

Publication types

MeSH terms

LinkOut - more resources