Structure-based design of bacterial nitric oxide synthase inhibitors

Holden, Jeffrey K.; Kang, Soosung; Hollingsworth, Scott A.; Li, Huiying; Lim, Nathan; Chen, Steven; Huang, He; Xue, Fengtian; Tang, Wei; Silverman, Richard B.; Poulos, Thomas L.

doi:10.1021/jm501723p

Structure-based design of bacterial nitric oxide synthase inhibitors

Journal Article · Wed Dec 17 23:00:00 EST 2014 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm501723p· OSTI ID:1347698

Holden, Jeffrey K. ^[1]; Kang, Soosung ^[2]; Hollingsworth, Scott A. ^[1]; Li, Huiying ^[1]; Lim, Nathan ^[1]; Chen, Steven ^[1]; Huang, He ^[2]; Xue, Fengtian ^[2]; Tang, Wei ^[2]; Silverman, Richard B. ^[2]; Poulos, Thomas L. ^[1]

Univ. of California, Irvine, CA (United States)
Northwestern Univ., Evanston, IL (United States)

Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge because of the near identical NOS active sites. One key structural difference between the NOS isoforms is the amino acid composition of the pterin cofactor binding site that is adjacent to the NOS active site. Previously, we demonstrated that a NOS inhibitor targeting both the active and pterin sites was potent and functioned as an antimicrobial. Here we present additional crystal structures, binding analyses, and bacterial killing studies of inhibitors that target both the active and pterin sites of a bNOS and function as antimicrobials. Lastly, these data provide a framework for continued development of bNOS inhibitors, as each molecule represents an excellent chemical scaffold for the design of isoform selective bNOS inhibitors.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of California, Irvine, CA (United States); Northwestern Univ., Evanston, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States)

OSTI ID:: 1347698

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 2 Vol. 58; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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