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Tytuł pozycji:

High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships.

Tytuł:
High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships.
Autorzy:
Frank H Niesen
Lena Schultz
Ajit Jadhav
Chitra Bhatia
Kunde Guo
David J Maloney
Ewa S Pilka
Minghua Wang
Udo Oppermann
Tom D Heightman
Anton Simeonov
Temat:
Medicine
Science
Źródło:
PLoS ONE, Vol 5, Iss 11, p e13719 (2010)
Wydawca:
Public Library of Science (PLoS), 2010.
Rok publikacji:
2010
Kolekcja:
LCC:Medicine
LCC:Science
Typ dokumentu:
article
Opis pliku:
electronic resource
Język:
English
ISSN:
1932-6203
Relacje:
http://europepmc.org/articles/PMC2970562?pdf=render; https://doaj.org/toc/1932-6203
DOI:
10.1371/journal.pone.0013719
Dostęp URL:
https://doaj.org/article/da1276c059c2465cb83ff8f287ef16f9  Link otwiera się w nowym oknie
Numer akcesji:
edsdoj.1276c059c2465cb83ff8f287ef16f9
Czasopismo naukowe
15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies.To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing >160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action.Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S2.

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