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Yin G, Lv G, Zhang J, et al. Early-stage structure-based drug discovery for small GTPases by NMR spectroscopy. Pharmacol Ther. 2022;108110doi: 10.1016/j.pharmthera.2022.108110.
Yin, G., Lv, G., Zhang, J., Jiang, H., Lai, T., Yang, Y., Ren, Y., Wang, J., Yi, C., Chen, H., Huang, Y., & Xiao, C. (2022). Early-stage structure-based drug discovery for small GTPases by NMR spectroscopy. Pharmacology & therapeutics, 108110. https://doi.org/10.1016/j.pharmthera.2022.108110
Yin, Guowei, et al. "Early-stage structure-based drug discovery for small GTPases by NMR spectroscopy." Pharmacology & therapeutics vol. (2022): 108110. doi: https://doi.org/10.1016/j.pharmthera.2022.108110
Yin G, Lv G, Zhang J, Jiang H, Lai T, Yang Y, Ren Y, Wang J, Yi C, Chen H, Huang Y, Xiao C. Early-stage structure-based drug discovery for small GTPases by NMR spectroscopy. Pharmacol Ther. 2022 Jan 07;108110. doi: 10.1016/j.pharmthera.2022.108110. Epub 2022 Jan 07. PMID: 35007659.
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Pharmacol Ther. 2022 Jan 07;108110. doi: 10.1016/j.pharmthera.2022.108110. Epub 2022 Jan 07.

Early-stage structure-based drug discovery for small GTPases by NMR spectroscopy.

Pharmacology & therapeutics

Guowei Yin, Guohua Lv, Jerry Zhang, Hongmei Jiang, Tianqi Lai, Yushan Yang, Yong Ren, Jing Wang, Chenju Yi, Hao Chen, Yun Huang, Chaoni Xiao

Affiliations

  1. The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: [email protected].
  2. Division of Histology & Embryology, Medical College, Jinan University, Guangzhou 511486, Guangdong, China.
  3. University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27516, USA.
  4. The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
  5. College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, China.
  6. Research Institute of Xi'an Jiaotong University, Hangzhou 311215, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China.
  7. Howard Hughes Medical Institute, Chevy Chase 20815, MD, USA; Department of Physiology & Biophysics, Weill Cornell Medicine, New York 10065, NY, USA. Electronic address: [email protected].
  8. College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, China. Electronic address: [email protected].

PMID: 35007659 DOI: 10.1016/j.pharmthera.2022.108110

Abstract

Small GTPase or Ras superfamily, including Ras, Rho, Rab, Ran and Arf, are fundamental in regulating a wide range of cellular processes such as growth, differentiation, migration and apoptosis. They share structural and functional similarities for binding guanine nucleotides and hydrolyzing GTP. Dysregulations of Ras proteins are involved in the pathophysiology of multiple human diseases, however there is still a stringent need for effective treatments targeting these proteins. For decades, small GTPases were recognized as 'undruggable' targets due to their complex regulatory mechanisms and lack of deep pockets for ligand binding. NMR has been critical in deciphering the structural and dynamic properties of the switch regions that are underpinning molecular switch functions of small GTPases, which pave the way for developing new effective inhibitors. The recent progress of drug or lead molecule development made for small GTPases profoundly delineated how modern NMR techniques reshape the field of drug discovery. In this review, we will summarize the progress of structural and dynamic studies of small GTPases, the NMR techniques developed for fragment-based drug screening and their applications in early-stage drug discovery for small GTPases.

Copyright © 2021. Published by Elsevier Inc.

Keywords: Drug discovery; Molecular switches; NMR; Small GTPases; Structure and dynamics

Conflict of interest statement

Declaration of Competing Interest The authors declare no conflict of interest.

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