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

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.

Graphical abstract

Keywords

Nitric oxide synthase / Endothelial NOS / Neuronal NOS / Drug design / Molecular pharmacology / Inducible NOS

Acknowledgements

We thank Prof Lin Liu, Prof Yuefeng Bi, Prof Wen Zhao and Prof Hongmin Liu etc. for help and software access, helpful discussions, etc. This project was supported by the National Natural Science Foundation of China (31900913). Thanks to the support from Shanghai Synchrotron Radiation Facility and National Facility for Protein Science Shanghai (NFPSS). Thanks to the support from the Postgraduate Education Reform Research Project of Zhengzhou university in 2021 (YJSJY202159), the Education Reform Research Project (for international students) of Zhengzhou University in 2022 (2022ZZUJGXMLXS-031), the Training Program of Innovation and Entrepreneurship for College Students (Undergraduate Research Training Program, 202310459149).

RIGHTS & PERMISSIONS

2023 The Author(s)