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Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-Carboximidamides

Li, Huiying and Evenson, Ryan J. and Chreifi, Georges and Silverman, Richard B. and Poulos, Thomas L. (2018) Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-Carboximidamides. Biochemistry, 57 (44). pp. 6319-6325. ISSN 0006-2960. http://resolver.caltech.edu/CaltechAUTHORS:20181023-091340888

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Abstract

The over production of nitric oxide in the brain by neuronal nitric oxide synthase (nNOS) is associated with a number of neurodegenerative diseases. Although inhibiting nNOS is an important therapeutic goal, it is important not to inhibit endothelial NOS (eNOS) owing to the critical role played by eNOS in maintaining vascular tone. While it has been possible to develop nNOS selective aminopyridine inhibitors, many of the most potent and selective inhibitors exhibit poor bioavailability properties. Our group and others have turned to more biocompatible thiophene-2-carboximidamides (T2C) inhibitors as potential nNOS selective inhibitors. We have used crystallography and computational methods to better understand how and why 2 commercially developed T2C inhibitors exhibit selectivity for human nNOS over human eNOS. As with many of the aminopyridine inhibitors, a critical active site Asp residue in nNOS vs Asn in eNOS is largely responsible for controlling selectivity. We also present thermodynamic integration results to better understand the change in pKa and thus charge of inhibitors once bound to the active site. In addition, relative free energy calculations underscore the importance of enhanced electrostatic stabilization of inhibitors bound to the nNOS active site compared to eNOS.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.biochem.8b00895DOIArticle
https://pubs.acs.org/doi/suppl/10.1021/acs.biochem.8b00895PublisherSupporting Information
ORCID:
AuthorORCID
Silverman, Richard B.0000-0001-9034-1084
Poulos, Thomas L.0000-0002-5648-3510
Additional Information:© 2018 American Chemical Society. Received: August 27, 2018; Revised: October 8, 2018; Published: October 17, 2018. Accession Codes: Coordinates and structure factors have been deposited in the Protein Data Bank as entries 6CIC, 6CID, 6CIE, and 6CIF. This work was supported by National Institutes of Health Grants GM57353 (T.L.P.) and GM049725 (R.B.S.). The authors declare no competing financial interest. The authors thank the Stanford Synchrotron Radiation Lab and the Advanced Light Source beamline staff for their support during remote X-ray diffraction data collection. The authors also acknowledge the San Diego Supercomputer Center.
Funders:
Funding AgencyGrant Number
NIHGM57353
NIHGM049725
Record Number:CaltechAUTHORS:20181023-091340888
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181023-091340888
Official Citation:Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-carboximidamides. Huiying Li, Ryan J. Evenson, Georges Chreifi, Richard B. Silverman, and Thomas L. Poulos. Biochemistry 2018 57 (44), 6319-6325. DOI: 10.1021/acs.biochem.8b00895
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90349
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Oct 2018 21:57
Last Modified:07 Nov 2018 22:09

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