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Structure-based development of novel adenylyl cyclase inhibitors.

Title data

Schlicker, Christine ; Rauch, Annika ; Hess, Ken C. ; Kachholz, Barbara ; Levin, Lonny R. ; Buck, Jochen ; Steegborn, Clemens:
Structure-based development of novel adenylyl cyclase inhibitors.
In: Journal of Medicinal Chemistry. Vol. 51 (14 August 2008) Issue 15 . - pp. 4456-4464.
ISSN 0022-2623
DOI: https://doi.org/10.1021/jm800481q

Abstract in another language

In mammals, the second messenger cAMP is synthesized by a family of transmembrane isoforms (tmACs) and one known cytoplasmic enzyme, "soluble" adenylyl cyclase (sAC). Understanding the individual contributions of these families to cAMP signaling requires tools which can distinguish them. Here, we describe the structure-based development of isoform discriminating AC inhibitors. Docking calculations using a library of small molecules with the crystal structure of a sAC homologue complexed with the noncompetitive inhibitor catechol estrogen identified two novel inhibitors, 3,20-dioxopregn-4-en-21-yl4-bromobenzenesulfonate (2) and 1,2,3,4,5,6,7,8,13,13,14,14-dodecachloro-1,4,4a,4b,5,8,8a,12b-octahydro-11-sulfo-1,4:5,8-dimethanotriphenylene-10-carboxylic acid (3). In vitro testing revealed that 3 defines a novel AC inhibitor scaffold with high affinity for human sAC and less inhibitory effect on mammalian tmACs. 2 also discriminates between sAC and tmACs, and it appears to simultaneously block the original binding pocket and a neighboring interaction site. Our results show that compounds exploiting the catechol estrogen binding site can produce potent, isoform discriminating AC inhibitors.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: PubMed-ID: 12609998
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 16 Apr 2015 11:31
Last Modified: 16 Apr 2015 11:31
URI: https://eref.uni-bayreuth.de/id/eprint/10294