Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds

Jianshu Dong; Dié Li; Lei Kang; Chenbing Luo; Jiangyun Wang

doi:10.52601/bpr.2023.210045

Volume 9 Issue 3

Jun. 2023

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Jianshu Dong, Dié Li, Lei Kang, Chenbing Luo, Jiangyun Wang. Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds. Biophysics Reports, 2023, 9(3): 159-175. doi: 10.52601/bpr.2023.210045

Citation:

Jianshu Dong, Dié Li, Lei Kang, Chenbing Luo, Jiangyun Wang. Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds. Biophysics Reports, 2023, 9(3): 159-175. doi: 10.52601/bpr.2023.210045

Citation:

Jianshu Dong, Dié Li, Lei Kang, Chenbing Luo, Jiangyun Wang. Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds. Biophysics Reports, 2023, 9(3): 159-175. doi: 10.52601/bpr.2023.210045

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Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds

doi: 10.52601/bpr.2023.210045

Jianshu Dong^{1, 2, 3, 4, 5
,
,},
Dié Li^{1, 2, 3, 4, 5},
Lei Kang^{1, 2, 3, 4, 5},
Chenbing Luo^{1, 2, 3, 4, 5},
Jiangyun Wang⁶

1.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
2.
Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China
3.
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China
4.
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou University, Zhengzhou 450001, China
5.
Key Laboratory of Henan Province for Drug Quality control and Evaluation, Zhengzhou University, Zhengzhou 450001, China
6.
Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

More Information

Corresponding author: jdong@zzu.edu.cn (J. Dong)
Received Date: 25 October 2021
Accepted Date: 18 May 2023

Available Online: 03 November 2023

Publish Date: 01 June 2023

Abstract

Abstract

83 Structures of human nNOS, 55 structures of human eNOS, 13 structures of iNOS, and about 126 reported NOS-bound compounds are summarized and analyzed. Structural and statistical analysis show that, at least one copy of each analyzed compound binds to the active site (the substrate arginine binding site) of human NOS. And binding features of the three isoforms show differences, but the binding preference of compounds is not in the way helpful for inhibitor design targeting nNOS and iNOS, or for activator design targeting eNOS. This research shows that there is a strong structural and functional similarity between oxygenase domains of human NOS isoforms, especially the architecture, residue composition, size, shape, and distribution profile of hydrophobicity, polarity and charge of the active site. The selectivity and efficacy of inhibitors over the rest of isoforms rely a lot on chance and randomness. Further increase of selectivity via rational improvement is uncertain, unpredictable and unreliable, therefore, to achieve high selectivity through targeting this site is complicated and requires combinative investigation. After analysis on the current two targeting sites in NOS, the highly conserved arginine binding pocket and H4B binding pocket, new potential drug-targeting sites are proposed based on structure and sequence profiling. This comprehensive analysis on the structure and interaction profiles of human NOS and bound compounds provides fresh insights for drug discovery and pharmacological research, and the new discovery here is practically applied to guide protein-structure based drug discovery.
- Nitric oxide synthase,
- Endothelial NOS,
- Neuronal NOS,
- Drug design,
- Molecular pharmacology,
- Inducible NOS

Jianshu Dong, Lei Kang, Dié Li, Chenbing Luo and Jiangyun Wang declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects performed by the any of the authors.

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