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

URLURL - Predstavitvena datoteka, za dostop obiščite http://www.sciencedirect.com/science/article/pii/S0223523411002960 Novo okno

Izvleček
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.

Jezik:Angleški jezik
Ključne besede:MurD inhibitorji, ko-kristalne strukture, optimizacija, D-glutaminska kislina, antibakterijsko delovanje
Vrsta gradiva:Delo ni kategorizirano (r6)
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2011
Št. strani:str. 2880-2894
Številčenje:Vol. 46, no. 7
UDK:542:615.2
ISSN pri članku:0223-5234
DOI:10.1016/j.ejmech.2011.04.011 Povezava se odpre v novem oknu
COBISS.SI-ID:3001457 Povezava se odpre v novem oknu
Število ogledov:345
Število prenosov:123
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Gradivo je del revije

Naslov:European journal of medicinal chemistry
Skrajšan naslov:Eur. j. med. chem.
Založnik:Elsevier
ISSN:0223-5234
COBISS.SI-ID:25429760 Novo okno

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