Second-generation sulfonamide inhibitors of d-glutamic acid-adding enzyme: activity optimisation with conformationally rigid analogues of d-glutamic acid
Sosič, Izidor (Author), Barreteau, Hélène (Author), Simčič, Mihael (Author), Šink, Roman (Author), Cesar, Jožko (Author), Zega, Anamarija (Author), Golič Grdadolnik, Simona (Author), Contreras Martel, Carlos (Author), Dessen, Andréa (Author), Amoroso, Ana (Author), Joris, Bernard (Author), Blanot, Didier (Author), Gobec, Stanislav (Author)

URLURL - Presentation file, Visit http://www.sciencedirect.com/science/article/pii/S0223523411002960 This link opens in a new window

D-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of D-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-L-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-DGlu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of D-Glu. The compounds that contained either constrained D-Glu or related rigid D-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities.

Keywords:MurD inhibitorji, ko-kristalne strukture, optimizacija, D-glutaminska kislina, antibakterijsko delovanje
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Number of pages:str. 2880-2894
Numbering:Vol. 46, no. 7
ISSN on article:0223-5234
DOI:10.1016/j.ejmech.2011.04.011 Link is opened in a new window
COBISS.SI-ID:3001457 Link is opened in a new window
Average score:(0 votes)
Your score:Voting is allowed only to logged in users.
AddThis uses cookies that require your consent. Edit consent...

Record is a part of a journal

Title:European journal of medicinal chemistry
Shortened title:Eur. j. med. chem.
COBISS.SI-ID:25429760 This link opens in a new window

Similar documents

Similar works from RUL:
Similar works from other Slovenian collections:


Leave comment

You have to log in to leave a comment.

Comments (0)
0 - 0 / 0
There are no comments!